|
1
|
Ailabouni A, Prasad B. Organic cation transporters 2: Structure, regulation, functions, and clinical implications. Drug Metab Dispos 2025; 53:100044. [PMID: 40020559 DOI: 10.1016/j.dmd.2025.100044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/21/2025] [Indexed: 03/03/2025] Open
Abstract
The SLC22A2 gene encodes organic cation transporter 2 (OCT2), which is predominantly expressed in renal proximal tubule cells. OCT2 is critical for the active renal excretion of various cationic drugs and endogenous metabolites. OCT2 expression varies across species, with higher levels in mice and monkeys compared with humans and rats. The human OCT2 protein consists of 555 amino acids and contains 12 transmembrane domains. OCT2 functions as a uniporter, facilitating the bidirectional transport of organic cations into renal tubular cells, driven by the inside-negative membrane potential. Its expression is regulated by sex hormones, contributing to potential sex differences in Oct2 activity in rodents. OCT2 has been linked to tissue toxicity, such as cisplatin-induced nephrotoxicity. Factors such as genetic variants, age, disease states, and the coadministration of drugs, including tyrosine kinase inhibitors, contribute to interindividual variability in OCT2 activity. This, in turn, impacts the systemic exposure and elimination of drugs and endogenous substances. Regulatory agencies recommend evaluating the potential of a drug to inhibit OCT2 through in vitro and clinical drug-drug interaction (DDI) studies, often using metformin as a probe substrate. Emerging tools like transporter biomarkers and physiologically based pharmacokinetic modeling hold promise in predicting OCT2-mediated DDIs. While several OCT2 biomarkers, such as N1-methylnicotinamide, have been proposed, their reliability in predicting renal DDIs remains uncertain and requires further study. Ultimately, a better understanding of the factors influencing OCT2 activity is essential for achieving precision medicine and minimizing renal and systemic toxicity. SIGNIFICANCE STATEMENT: Organic cation transporter 2 (OCT2) is essential for the active tubular secretion of xenobiotics and endogenous cationic substances in the kidneys. This article offers a comprehensive overview of the tissue distribution, interspecies differences, and factors affecting its activity-critical for evaluating tissue toxicity and systemic exposure to cationic substances. Using OCT2 biomarkers and integrating OCT2 activity and expression data into physiologically based pharmacokinetic models are valuable tools for predicting OCT2 function and its clinical implications.
Collapse
Affiliation(s)
- Anoud Ailabouni
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Bhagwat Prasad
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington.
| |
Collapse
|
|
2
|
Babu T, Muthuramalingam RPK, Chng WH, Yau JNN, Acharya S, Engelmayer N, Feldman-Goriachnik R, Lev S, Pastorin G, Binshtok A, Hanani M, Gibson D. Multitargeting Pt(IV) Derivatives of Cisplatin or Oxaliplatin Inhibit Tumor Growth in Mice without Inducing Neuropathic Pain. J Med Chem 2025; 68:1608-1618. [PMID: 39779280 PMCID: PMC11770746 DOI: 10.1021/acs.jmedchem.4c02263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 12/22/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025]
Abstract
Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropathy (PN) that affects ∼70% of patients. PN is caused by selective accumulation of the platinum drugs in the dorsal root ganglia (DRG), which overexpress transporters for cisplatin and oxaliplatin. To date, no drug is recommended for the prevention of PN. We report that Pt(IV) prodrugs of cisplatin or oxaliplatin do not induce neuropathic pain in mice, likely due to the lower accumulation of platinum in the DRG compared with Pt(II) drugs. Moreover, the multitargeting prodrug that combines cisplatin with paclitaxel, both strong inducers of PN, efficiently inhibited tumor growth in vivo without inducing neuropathic pain. The high antitumor efficacy of Pt(IV) prodrugs and their micellar counterparts and the low level of neuropathic pain associated with them make them ideal candidates for clinical use in cancer therapy.
Collapse
Affiliation(s)
- Tomer Babu
- Institute
for Drug Research, School of Pharmacy, The
Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ram Pravin Kumar Muthuramalingam
- Department
of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117544, Singapore
| | - Wei Heng Chng
- Department
of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117544, Singapore
| | - Jia Ning Nicolette Yau
- Department
of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117544, Singapore
| | - Sourav Acharya
- Institute
for Drug Research, School of Pharmacy, The
Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Nurit Engelmayer
- Department
of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel
- The
Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
| | - Rachel Feldman-Goriachnik
- Laboratory
of Experimental Surgery, Hadassah-Hebrew
University Medical Center, Mount Scopus, Jerusalem 91240, Israel
- Faculty of
Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Shaya Lev
- Department
of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel
- The
Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
| | - Giorgia Pastorin
- Department
of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117544, Singapore
| | - Alexander Binshtok
- Department
of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel
- The
Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
| | - Menachem Hanani
- Laboratory
of Experimental Surgery, Hadassah-Hebrew
University Medical Center, Mount Scopus, Jerusalem 91240, Israel
- Faculty of
Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Dan Gibson
- Institute
for Drug Research, School of Pharmacy, The
Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| |
Collapse
|
|
3
|
Yamane F, Ikemura K, Kondo M, Ueno M, Okuda M. Identification of dequalinium as a potent inhibitor of human organic cation transporter 2 by machine learning based QSAR model. Sci Rep 2025; 15:2581. [PMID: 39833227 PMCID: PMC11746930 DOI: 10.1038/s41598-024-79377-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/08/2024] [Indexed: 01/22/2025] Open
Abstract
Human organic cation transporter 2 (hOCT2/SLC22A2) is a key drug transporter that facilitates the transport of endogenous and exogenous organic cations. Because hOCT2 is responsible for the development of adverse effects caused by platinum-based anti-cancer agents, drugs with OCT2 inhibitory effects may serve as prophylactic agents against the toxicity of platinum-based anti-cancer agents. In the present study, we established a machine learning-based quantitative structure-activity relationship (QSAR) model for hOCT2 inhibitors based on the public ChEMBL database and explored novel hOCT2 inhibitors among the FDA-approved drugs. Using our QSAR model, we identified 162 candidate hOCT2 inhibitors among the FDA-approved drugs registered in the DrugBank database. After manual selection and in vitro assays, we found that dequalinium, a quaternary ammonium cation antimicrobial agent, is a potent hOCT2 inhibitor (IC50 = 88.16 ± 7.14 nM). Moreover, dequalinium inhibited hOCT2-mediated transport of platinum anti-cancer agents (cisplatin and oxaliplatin) in a concentration-dependent manner. Our study is the first to demonstrate the construction of a novel machine learning-based QSAR model for hOCT2 inhibitors and identify a novel hOCT2 inhibitor among FDA-approved drugs using this model.
Collapse
Affiliation(s)
- Fumihiro Yamane
- Department of Hospital Pharmacy, School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Kenji Ikemura
- Department of Pharmacy, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Masayoshi Kondo
- Department of Hospital Pharmacy, School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Manami Ueno
- Department of Hospital Pharmacy, School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Masahiro Okuda
- Department of Pharmacy, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan
| |
Collapse
|
|
4
|
Bhilare KD, Dobariya P, Hanak F, Rothwell PE, More SS. Current understanding of the link between angiotensin-converting enzyme and pain perception. Drug Discov Today 2024; 29:104089. [PMID: 38977123 PMCID: PMC11368640 DOI: 10.1016/j.drudis.2024.104089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/27/2024] [Accepted: 07/03/2024] [Indexed: 07/10/2024]
Abstract
The renin-angiotensin system (RAS) is known to affect diverse physiological processes that affect the functioning of many key organs. Angiotensin-converting enzyme (ACE) modulates a variety of bioactive peptides associated with pain. ACE inhibitors (ACEis) have found applications in the treatment of cardiovascular, kidney, neurological and metabolic disorders. However, ACEis also tend to display undesirable effects, resulting in increased pain sensitization and mechanical allodynia. In this review, we provide comprehensive discussion of preclinical and clinical studies involving the evaluation of various clinically approved ACEis. With the emerging knowledge of additional factors involved in RAS signaling and the indistinct pharmacological role of ACE substrates in pain, extensive studies are still required to elucidate the mechanistic role of ACE in pain perception.
Collapse
Affiliation(s)
- Kiran D Bhilare
- Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
| | - Prakashkumar Dobariya
- Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
| | - Filip Hanak
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Patrick E Rothwell
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Swati S More
- Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
| |
Collapse
|
|
5
|
Ahmed Eltayeb S, Dressler JM, Schlatt L, Pernecker M, Neugebauer U, Karst U, Ciarimboli G. Interaction of the chemotherapeutic agent oxaliplatin and the tyrosine kinase inhibitor dasatinib with the organic cation transporter 2. Arch Toxicol 2024; 98:2131-2142. [PMID: 38589558 PMCID: PMC11169033 DOI: 10.1007/s00204-024-03742-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 03/18/2024] [Indexed: 04/10/2024]
Abstract
Oxaliplatin (OHP) is effective in colorectal cancer treatment but induces peripheral neurotoxicity (OHP-induced peripheral neurotoxicity, OIPN), diminishing survivor quality of life. Organic cation transporter 2 (OCT2) is a key OHP uptake pathway in dorsal root ganglia. Competing for OCT2-mediated OHP uptake, such as with the tyrosine kinase inhibitor dasatinib, may mitigate OHP side effects. We investigated OHP and dasatinib interaction with OCT2 in human embryonic kidney 293 (HEK293) cells expressing OCT2 within a 10-3 to 10-7 M concentration range. Uptake competition experiments using fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (ASP+, 1 µM) and mass spectrometry (MS) to determine cellular platinum content indicated that OHP (100 µM) is an OCT2 substrate, mediating OHP cellular toxicity. ASP+ and MS analysis revealed dasatinib as a non-transported inhibitor of hOCT2 (IC50 = 5.9 µM) and as a regulator of OCT2 activity. Dasatinib reduced transporter Vmax, potentially via Y544 phosphorylation suppression. MS analysis showed cellular dasatinib accumulation independent of hOCT2. Although 3 µM dasatinib reduced 100 µM OHP accumulation in hOCT2-HEK293 cells, co-incubation with dasatinib and OHP did not prevent OHP toxicity, possibly due to dasatinib-induced cell viability reduction. In summary, this study demonstrates OHP as an OCT2 substrate and dasatinib as a non-transported inhibitor and regulator of OCT2, offering potential for OIPN mitigation.
Collapse
Affiliation(s)
- Sara Ahmed Eltayeb
- Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1/A14, 48149, Münster, Germany
| | - Julia M Dressler
- Institut Für Anorganische Und Analytische Chemie, Universität Münster, Münster, Germany
| | - Lukas Schlatt
- Institut Für Anorganische Und Analytische Chemie, Universität Münster, Münster, Germany
| | - Moritz Pernecker
- Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1/A14, 48149, Münster, Germany
| | - Ute Neugebauer
- Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1/A14, 48149, Münster, Germany
| | - Uwe Karst
- Institut Für Anorganische Und Analytische Chemie, Universität Münster, Münster, Germany
| | - Giuliano Ciarimboli
- Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1/A14, 48149, Münster, Germany.
| |
Collapse
|
|
6
|
Du J, Sudlow LC, Luzhansky ID, Berezin MY. DRG Explant Model: Elucidating Mechanisms of Oxaliplatin-Induced Peripheral Neuropathy and Identifying Potential Therapeutic Targets. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.05.560580. [PMID: 37873159 PMCID: PMC10592953 DOI: 10.1101/2023.10.05.560580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Oxaliplatin triggered chemotherapy induced peripheral neuropathy (CIPN) is a common and debilitating side effect of cancer treatment which limits the efficacy of chemotherapy and negatively impacts patients quality of life dramatically. For better understanding the mechanisms of CIPN and screen for potential therapeutic targets, it is critical to have reliable in vitro assays that effectively mirror the neuropathy in vivo . In this study, we established a dorsal root ganglia (DRG) explant model. This model displayed dose-dependent inhibition of neurite outgrowth in response to oxaliplatin, while oxalic acid exhibited no significant impact on the regrowth of DRG. The robustness of this assay was further demonstrated by the inhibition of OCT2 transporter, which facilitates oxaliplatin accumulation in neurons, fully restoring the neurite regrowth capacity. Using this model, we revealed that oxaliplatin triggered a substantial increase of oxidative stress in DRG. Notably, inhibition of TXNIP with verapamil significantly reduced oxidative stress level. Our results demonstrated the use of DRG explants as an efficient model to study the mechanisms of CIPN and screen for potential treatments.
Collapse
|
|
7
|
Kurt B, Sipahi Karslı Z, Fernández-Ortega P, Çakmak Öksüzoğlu BÖ. Experiences and Perceptions of Patients with Oxaliplatin-Induced Cold Sensitivity in Turkey: A Qualitative Study. Semin Oncol Nurs 2023; 39:151479. [PMID: 37543469 DOI: 10.1016/j.soncn.2023.151479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 06/12/2023] [Accepted: 07/03/2023] [Indexed: 08/07/2023]
Abstract
OBJECTIVES This study aimed to explore and describe the impact on patients with oxaliplatin-induced cold sensitivity in the early stages. DATA SOURCES An inductive design was used for this qualitative study, which included open-ended, and in-depth interviews with 18 cancer patients. Throughout the study, the authors followed the COREQ checklist. The interviews were audiorecorded and listened to multiple times. Observation notes were also recorded following each interview. Thematic analysis developed six main themes and 13 subthemes. The first theme concerns changing habits, including changes in fluid intake and clothing choice, changes in bathing and eating habits, and changes in caregiver roles. The second theme includes changes in daily routine behaviors that are perceived as difficulties with changing routines. The third theme is avoiding triggers; the fourth theme is anxiety about self-care. The fifth theme includes a subtheme of difficulty in contact. The final theme includes adaptation to life, caring responsibilities, changes in sexual functions, the performance of religious activities, and social activities IMPLICATIONS FOR NURSING PRACTICE: This study provides an overview of the lived experiences of oxaliplatin-induced cold sensitivity among cancer patients. Patients faced fewer adverse events by avoiding initiators from the first treatment. They changed their eating and drinking habits owing to difficulties. The findings of this study can be used to better understand oxaliplatin-induced cold sensitivity, identify patients needs based on their experience, and develop interventions to improve patient outcomes.
Collapse
Affiliation(s)
- Berna Kurt
- Nursing Faculty, Department of Internal Medical Nursing, Hacettepe University, Ankara, Turkey.
| | - Zeynep Sipahi Karslı
- Department of Medical Oncology, Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey
| | - Paz Fernández-Ortega
- Department of Nursing Sciences, Catalan Institute of Oncology and University of Barcelona, Spain
| | - Berna Ömür Çakmak Öksüzoğlu
- Department of Medical Oncology, Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey
| |
Collapse
|
|
8
|
Cheng F, Zhang R, Sun C, Ran Q, Zhang C, Shen C, Yao Z, Wang M, Song L, Peng C. Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies. Front Pharmacol 2023; 14:1231401. [PMID: 37593174 PMCID: PMC10427877 DOI: 10.3389/fphar.2023.1231401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/18/2023] [Indexed: 08/19/2023] Open
Abstract
Oxaliplatin-based chemotherapy is a standard treatment approach for colorectal cancer (CRC). However, oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe dose-limiting clinical problem that might lead to treatment interruption. This neuropathy may be reversible after treatment discontinuation. Its complicated mechanisms are related to DNA damage, dysfunction of voltage-gated ion channels, neuroinflammation, transporters, oxidative stress, and mitochondrial dysfunction, etc. Several strategies have been proposed to diminish OIPN without compromising the efficacy of adjuvant therapy, namely, combination with chemoprotectants (such as glutathione, Ca/Mg, ibudilast, duloxetine, etc.), chronomodulated infusion, dose reduction, reintroduction of oxaliplatin and topical administration [hepatic arterial infusion chemotherapy (HAIC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and hyperthermic intraperitoneal chemotherapy (HIPEC)]. This article provides recent updates related to the potential mechanisms, therapeutic strategies in treatment of OIPN, and pharmacokinetics of several methods of oxaliplatin administration in clinical trials.
Collapse
Affiliation(s)
- Fang Cheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ruoqi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chen Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Ran
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cuihan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Changhong Shen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ziqing Yao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Miao Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lin Song
- Department of Pharmacy, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
9
|
Hucke A, Schröter R, Ceresa C, Chiorazzi A, Canta A, Semperboni S, Marmiroli P, Cavaletti G, Gess B, Ciarimboli G. Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin. Int J Mol Sci 2023; 24:11486. [PMID: 37511245 PMCID: PMC10380567 DOI: 10.3390/ijms241411486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/06/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2-/- mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2-/- mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2-/- mice). Comparing the apparent affinities (IC50) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC50: 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP.
Collapse
Affiliation(s)
- Anna Hucke
- Experimentelle Nephrologie, Medizinische Klinik D, Universitätsklinikum Münster, 48149 Münster, Germany; (A.H.); (R.S.)
| | - Rita Schröter
- Experimentelle Nephrologie, Medizinische Klinik D, Universitätsklinikum Münster, 48149 Münster, Germany; (A.H.); (R.S.)
| | - Cecilia Ceresa
- Experimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy; (C.C.); (A.C.); (A.C.); (S.S.); (P.M.); (G.C.)
| | - Alessia Chiorazzi
- Experimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy; (C.C.); (A.C.); (A.C.); (S.S.); (P.M.); (G.C.)
| | - Annalisa Canta
- Experimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy; (C.C.); (A.C.); (A.C.); (S.S.); (P.M.); (G.C.)
| | - Sara Semperboni
- Experimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy; (C.C.); (A.C.); (A.C.); (S.S.); (P.M.); (G.C.)
| | - Paola Marmiroli
- Experimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy; (C.C.); (A.C.); (A.C.); (S.S.); (P.M.); (G.C.)
| | - Guido Cavaletti
- Experimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy; (C.C.); (A.C.); (A.C.); (S.S.); (P.M.); (G.C.)
- Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Burkhard Gess
- Department of Neurology, University Hospital Münster, 48149 Münster, Germany;
- Department of Neurology, Evangelisches Klinikum Bethel, University of Bielefeld, 33617 Bielefeld, Germany
| | - Giuliano Ciarimboli
- Experimentelle Nephrologie, Medizinische Klinik D, Universitätsklinikum Münster, 48149 Münster, Germany; (A.H.); (R.S.)
| |
Collapse
|
|
10
|
Dhakne P, Pillai M, Mishra S, Chatterjee B, Tekade RK, Sengupta P. Refinement of safety and efficacy of anti-cancer chemotherapeutics by tailoring their site-specific intracellular bioavailability through transporter modulation. Biochim Biophys Acta Rev Cancer 2023; 1878:188906. [PMID: 37172652 DOI: 10.1016/j.bbcan.2023.188906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/20/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023]
Abstract
Low intracellular bioavailability, off-site toxicities, and multi drug resistance (MDR) are the major constraints involved in cancer chemotherapy. Many anticancer molecules fail to become a good lead in drug discovery because of their poor site-specific bioavailability. Concentration of a molecule at target sites is largely varied because of the wavering expression of transporters. Recent anticancer drug discovery strategies are paying high attention to enhance target site bioavailability by modulating drug transporters. The level of genetic expression of transporters is an important determinant to understand their ability to facilitate drug transport across the cellular membrane. Solid carrier (SLC) transporters are the major influx transporters involved in the transportation of most anti-cancer drugs. In contrast, ATP-binding cassette (ABC) superfamily is the most studied class of efflux transporters concerning cancer and is significantly involved in efflux of chemotherapeutics resulting in MDR. Balancing SLC and ABC transporters is essential to avoid therapeutic failure and minimize MDR in chemotherapy. Unfortunately, comprehensive literature on the possible approaches of tailoring site-specific bioavailability of anticancer drugs through transporter modulation is not available till date. This review critically discussed the role of different specific transporter proteins in deciding the intracellular bioavailability of anticancer molecules. Different strategies for reversal of MDR in chemotherapy by incorporation of chemosensitizers have been proposed in this review. Targeted strategies for administration of the chemotherapeutics to the intracellular site of action through clinically relevant transporters employing newer nanotechnology-based formulation platforms have been explained. The discussion embedded in this review is timely considering the current need of addressing the ambiguity observed in pharmacokinetic and clinical outcomes of the chemotherapeutics in anti-cancer treatment regimens.
Collapse
Affiliation(s)
- Pooja Dhakne
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Megha Pillai
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Sonam Mishra
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Bappaditya Chatterjee
- SVKM's NMIMS School of Pharmacy and Management, Department of Pharmaceutics, Vaikunthlal Mehta Road, Vile Parle West, Mumbai, Maharashtra 400056, India
| | - Rakesh K Tekade
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Pinaki Sengupta
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India.
| |
Collapse
|
|
11
|
Shin KH, Lee KR, Kang MJ, Chae YJ. Strong inhibition of organic cation transporter 2 by flavonoids and attenuation effects on cisplatin-induced cytotoxicity. Chem Biol Interact 2023; 379:110504. [PMID: 37084994 DOI: 10.1016/j.cbi.2023.110504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 04/23/2023]
Abstract
Organic cation transporter 2 (OCT2) is predominantly expressed in the basolateral membrane of renal proximal tubule cells and contributes to the renal excretion of various drugs such as metformin, cisplatin, oxaliplatin, cimetidine, and lamivudine. Cisplatin, an anticancer agent for various cancers, is a substrate of OCT2, and cisplatin-induced nephrotoxicity is in part attributed to OCT2 activity in the kidney, which increases the renal accumulation of cisplatin. In this study, we aimed to identify flavone derivatives with strong inhibitory effects on OCT2 transport. Among the 80 flavonoids tested, 24 showed moderate to strong inhibitory effects against OCT2 transport activity. The IC50 values were less than 5 μM for 10 flavonoids. All 10 compounds alleviated cisplatin-induced cytotoxicity in cells expressing OCT2, even though the magnitude of the effects varied depending on the functional moieties in each position. Multiple factor analysis revealed that the methyl group at the R1 position and methoxy group at the R6 position of the flavonol backbone are important for OCT2 inhibition. Information on the functional moieties in the flavonol backbone would help develop effective OCT2 inhibitors by providing a structural association with OCT2 inhibitory effects. In addition, the compounds with strong inhibitory effects on OCT2 identified in this study may be potential candidates for clinical use to mitigate cisplatin-induced nephrotoxicity.
Collapse
Affiliation(s)
- Kwang-Hee Shin
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, South Korea
| | - Kyeong-Ryoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, South Korea; Department of Bioscience, University of Science and Technology, Daejeon, 34113, South Korea
| | - Min-Ji Kang
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju, 55338, South Korea
| | - Yoon-Jee Chae
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju, 55338, South Korea.
| |
Collapse
|
|
12
|
Puris E, Fricker G, Gynther M. The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy. Pharmaceutics 2023; 15:pharmaceutics15020364. [PMID: 36839686 PMCID: PMC9966068 DOI: 10.3390/pharmaceutics15020364] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells.
Collapse
|
|
13
|
The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of Tyrosine Kinase Inhibitors. Int J Mol Sci 2023; 24:ijms24032101. [PMID: 36768423 PMCID: PMC9917293 DOI: 10.3390/ijms24032101] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) decisively contributed in revolutionizing the therapeutic approach to cancer, offering non-invasive, tolerable therapies for a better quality of life. Nonetheless, degree and duration of the response to TKI therapy vary depending on cancer molecular features, the ability of developing resistance to the drug, on pharmacokinetic alterations caused by germline variants and unwanted drug-drug interactions at the level of membrane transporters and metabolizing enzymes. A great deal of approved TKIs are inhibitors of the organic cation transporters (OCTs). A handful are also substrates of them. These transporters are polyspecific and highly expressed in normal epithelia, particularly the intestine, liver and kidney, and are, hence, arguably relevant sites of TKI interactions with other OCT substrates. Moreover, OCTs are often repressed in cancer cells and might contribute to the resistance of cancer cells to TKIs. This article reviews the OCT interactions with approved and in-development TKIs reported in vitro and in vivo and critically discusses the potential clinical ramifications thereof.
Collapse
|
|
14
|
Kantauskaite M, Hucke A, Snieder B, Ciarimboli G. Exacerbation of Cisplatin Cellular Toxicity by Regulation of the Human Organic Cation Transporter 2 through Angiotensin II. Int J Mol Sci 2022; 23:ijms232415866. [PMID: 36555515 PMCID: PMC9779897 DOI: 10.3390/ijms232415866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/30/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Cisplatin (CDDP) is an efficient chemotherapeutic drug, whose use is associated with the development of serious undesired toxicities, such as nephrotoxicity. The human organic cation transporter 2 (hOCT2), which is highly expressed in the basolateral membrane domain of renal proximal tubules seems to play an important role in the development of CDDP nephrotoxicity. The role of angiotensin II (AII) signaling by binding to the AII receptor type 1 (AT1R) in the development and/or progression of CDDP nephrotoxicity is debated. Therefore, in this work, the regulation of hOCT2 activity by AII and its role in the development of CDDP cellular toxicity was investigated. To do this, hOCT2 was overexpressed by viral transduction in Madin-Darby Canine Kidney (MDCK) cells which were cultivated on a filter. This approach allows the separation of an apical and a basolateral membrane domain, which are easily accessible for experimentation. In this system, hOCT2 was mainly localized on the basolateral plasma membrane domain of the cells. The transporter was functional since a specific uptake of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+) with an affinity (Km) of 35 µM was only detectable by the addition of ASP+ to the basolateral compartment of hOCT2 expressing MDCK (hOCT2-MDCK) cells. Similarly, CDDP toxicity was evident mainly by CDDP addition to the basolateral compartment of hOCT2-MDCK cells cultivated on a filter. The addition of 1 nM AII stimulated hOCT2 function via PKC activation and worsened CDDP cytotoxicity via binding to AT1R. Therefore, the AII signaling pathway may be implicated in the development and/or progression of CDDP nephrotoxicity. This signaling pathway may be a target for protective interventions for example by blocking AT1R in the kidneys. However, it should be further investigated whether these findings obtained in a cell culture system may have translational relevance for the clinical situation. For toxicity experiments, a 100 µM CDDP concentration was used, which is high but allows us to identify clearly toxic effects due to hOCT2. In summary, down-regulation of hOCT2 activity by the inhibition of the AII signaling pathway may protect against CDDP nephrotoxicity.
Collapse
Affiliation(s)
- Marta Kantauskaite
- Experimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Anna Hucke
- Experimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany
- Institute of Physiology II, University of Münster, 48149 Münster, Germany
| | - Beatrice Snieder
- Experimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany
| | - Giuliano Ciarimboli
- Experimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany
- Correspondence: ; Tel.: +49-251-83-56981
| |
Collapse
|
|
15
|
Nepal MR, Taheri H, Li Y, Talebi Z, Uddin ME, Jin Y, DiGiacomo DF, Gibson AA, Lustberg MB, Hu S, Sparreboom A. Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-Induced Peripheral Neurotoxicity. CANCER RESEARCH COMMUNICATIONS 2022; 2:1334-1343. [PMID: 36506732 PMCID: PMC9730833 DOI: 10.1158/2767-9764.crc-22-0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts ~90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in DRG neurons. The antidepressant drug duloxetine has been used to treat OIPN, although its usefulness in preventing this side effect remains unclear. We hypothesized that duloxetine has OCT2-inhibitory properties and can be used as an adjunct to oxaliplatin-based regimens to prevent OIPN. Transport studies were performed in cells stably transfected with mouse or human OCT2 and in isolated mouse DRG neurons ex vivo. Wild-type and OCT2-deficient mice were used to assess effects of duloxetine on hallmarks of OIPN, endogenous OCT2 biomarkers, and the pharmacokinetics of oxaliplatin, and the translational feasibility of a duloxetine-oxaliplatin combination was evaluated in various models of colorectal cancer. We found that duloxetine potently inhibited the OCT2-mediated transport of several xenobiotic substrates, including oxaliplatin, in a reversible, concentration-dependent manner, and independent of species and cell context. Furthermore, duloxetine restricted access of these substrates to DRG neurons ex vivo and prevented OIPN in wild-type mice to a degree similar to the complete protection observed in OCT2-deficient mice, without affecting the plasma levels of oxaliplatin. Importantly, the uptake and cytotoxicity of oxaliplatin in tumor cell lines in vitro and in vivo were not negatively influenced by duloxetine. The observed OCT2-targeting properties of duloxetine, combined with the potential for clinical translation, provide support for its further exploration as a therapeutic candidate for studies aimed at preventing OIPN in cancer patients requiring treatment with oxaliplatin. Significance We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pre-treatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.
Collapse
Affiliation(s)
- Mahesh R. Nepal
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Division of Outcomes and Translational Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Hanieh Taheri
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Division of Outcomes and Translational Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Yang Li
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Division of Outcomes and Translational Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Zahra Talebi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Muhammad Erfan Uddin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Yan Jin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Duncan F. DiGiacomo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Alice A. Gibson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Maryam B. Lustberg
- The Breast Center at Smilow Cancer Hospital at Yale, Yale School of Medicine, New Haven, Connecticut
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Division of Outcomes and Translational Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Corresponding Authors: Shuiying Hu, Division of Outcomes and Translational Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, 496 West 12th Avenue, Columbus, Ohio, 43210. Phone: 614-247-6203; Fax: 614-688-4028; E-mail: ; and Alex Sparreboom, Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, 496 West 12th Avenue, The Ohio State University, Columbus, Ohio, 43210. E-mail:
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Corresponding Authors: Shuiying Hu, Division of Outcomes and Translational Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, 496 West 12th Avenue, Columbus, Ohio, 43210. Phone: 614-247-6203; Fax: 614-688-4028; E-mail: ; and Alex Sparreboom, Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, 496 West 12th Avenue, The Ohio State University, Columbus, Ohio, 43210. E-mail:
| |
Collapse
|
|
16
|
Tay N, Laakso EL, Schweitzer D, Endersby R, Vetter I, Starobova H. Chemotherapy-induced peripheral neuropathy in children and adolescent cancer patients. Front Mol Biosci 2022; 9:1015746. [PMID: 36310587 PMCID: PMC9614173 DOI: 10.3389/fmolb.2022.1015746] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 09/20/2022] [Indexed: 11/22/2022] Open
Abstract
Brain cancer and leukemia are the most common cancers diagnosed in the pediatric population and are often treated with lifesaving chemotherapy. However, chemotherapy causes severe adverse effects and chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and debilitating side effect. CIPN can greatly impair quality of life and increases morbidity of pediatric patients with cancer, with the accompanying symptoms frequently remaining underdiagnosed. Little is known about the incidence of CIPN, its impact on the pediatric population, and the underlying pathophysiological mechanisms, as most existing information stems from studies in animal models or adult cancer patients. Herein, we aim to provide an understanding of CIPN in the pediatric population and focus on the 6 main substance groups that frequently cause CIPN, namely the vinca alkaloids (vincristine), platinum-based antineoplastics (cisplatin, carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), epothilones (ixabepilone), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). We discuss the clinical manifestations, assessments and diagnostic tools, as well as risk factors, pathophysiological processes and current pharmacological and non-pharmacological approaches for the prevention and treatment of CIPN.
Collapse
Affiliation(s)
- Nicolette Tay
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - E-Liisa Laakso
- Mater Research Institute-The University of Queensland, South Brisbane, QLD, Australia
| | - Daniel Schweitzer
- Mater Research Institute-The University of Queensland, South Brisbane, QLD, Australia
| | - Raelene Endersby
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | - Irina Vetter
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
- The School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia
| | - Hana Starobova
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
- *Correspondence: Hana Starobova,
| |
Collapse
|
|
17
|
Organic cation transporter 2 activation enhances sensitivity to oxaliplatin in human pancreatic ductal adenocarcinoma. Biomed Pharmacother 2022; 153:113520. [DOI: 10.1016/j.biopha.2022.113520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/31/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022] Open
|
|
18
|
Uddin ME, Eisenmann ED, Li Y, Huang KM, Garrison DA, Talebi Z, Gibson AA, Jin Y, Nepal M, Bonilla IM, Fu Q, Sun X, Millar A, Tarasov M, Jay CE, Cui X, Einolf HJ, Pelis RM, Smith SA, Radwański PB, Sweet DH, König J, Fromm MF, Carnes CA, Hu S, Sparreboom A. MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia. Int J Mol Sci 2022; 23:8607. [PMID: 35955741 PMCID: PMC9369325 DOI: 10.3390/ijms23158607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 07/30/2022] [Accepted: 07/30/2022] [Indexed: 02/04/2023] Open
Abstract
Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.
Collapse
Affiliation(s)
- Muhammad Erfan Uddin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Eric D. Eisenmann
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Yang Li
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Kevin M. Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Dominique A. Garrison
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Zahra Talebi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Alice A. Gibson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Yan Jin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Mahesh Nepal
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Ingrid M. Bonilla
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA;
| | - Qiang Fu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Xinxin Sun
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| | - Alec Millar
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (A.M.); (M.T.); (P.B.R.); (C.A.C.); (S.H.)
| | - Mikhail Tarasov
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (A.M.); (M.T.); (P.B.R.); (C.A.C.); (S.H.)
| | - Christopher E. Jay
- Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA; (C.E.J.); (D.H.S.)
| | - Xiaoming Cui
- Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA; (X.C.); (H.J.E.); (R.M.P.)
| | - Heidi J. Einolf
- Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA; (X.C.); (H.J.E.); (R.M.P.)
| | - Ryan M. Pelis
- Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA; (X.C.); (H.J.E.); (R.M.P.)
| | - Sakima A. Smith
- OSU Wexner Medical Center, Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH 43210, USA;
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
| | - Przemysław B. Radwański
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (A.M.); (M.T.); (P.B.R.); (C.A.C.); (S.H.)
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
| | - Douglas H. Sweet
- Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA; (C.E.J.); (D.H.S.)
| | - Jörg König
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (J.K.); (M.F.F.)
| | - Martin F. Fromm
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (J.K.); (M.F.F.)
| | - Cynthia A. Carnes
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (A.M.); (M.T.); (P.B.R.); (C.A.C.); (S.H.)
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
- Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
| | - Shuiying Hu
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (A.M.); (M.T.); (P.B.R.); (C.A.C.); (S.H.)
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (E.D.E.); (Y.L.); (K.M.H.); (D.A.G.); (Z.T.); (A.A.G.); (Y.J.); (M.N.); (Q.F.); (X.S.)
| |
Collapse
|
|
19
|
Hafey MJ, Aleksunes LM, Bridges CC, Brouwer KR, Chien HC, Leslie EM, Hu S, Li Y, Shen J, Sparreboom A, Sprowl J, Tweedie D, Lai Y. Transporters and Toxicity: Insights from the International Transporter Consortium Workshop 4. Clin Pharmacol Ther 2022; 112:527-539. [PMID: 35546260 DOI: 10.1002/cpt.2638] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/30/2022] [Indexed: 12/29/2022]
Abstract
Over the last decade, significant progress been made in elucidating the role of membrane transporters in altering drug disposition, with important toxicological consequences due to changes in localized concentrations of compounds. The topic of "Transporters and Toxicity" was recently highlighted as a scientific session at the International Transporter Consortium (ITC) Workshop 4 in 2021. The current white paper is not intended to be an extensive review on the topic of transporters and toxicity but an opportunity to highlight aspects of the role of transporters in various toxicities with clinically relevant implications as covered during the session. This includes a review of the role of solute carrier transporters in anticancer drug-induced organ injury, transporters as key players in organ barrier function, and the role of transporters in metal/metalloid toxicity.
Collapse
Affiliation(s)
- Michael J Hafey
- ADME and Discovery Toxicology, Merck & Co., Inc., Rahway, New Jersey, USA
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Christy C Bridges
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, Georgia, USA
| | | | - Huan-Chieh Chien
- Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California, USA
| | - Elaine M Leslie
- Departments of Physiology and Lab Med and Path, Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada
| | - Shuiying Hu
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Yang Li
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Jinshan Shen
- Relay Therapeutics, Cambridge, Massachusetts, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Jason Sprowl
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
| | | | - Yurong Lai
- Drug Metabolism, Gilead Sciences Inc., Foster City, California, USA
| |
Collapse
|
|
20
|
Shankara Narayanan JSN, Frizzi K, Erdem S, Ray P, Jaroch D, Cox B, Katz S, Vicente D, White R. Oxaliplatin-induced peripheral neuropathy can be minimized by pressurized regional intravascular delivery in an orthotopic murine pancreatic cancer model. Discov Oncol 2022; 13:21. [PMID: 35384564 PMCID: PMC8986945 DOI: 10.1007/s12672-022-00483-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/23/2022] [Indexed: 12/03/2022] Open
Abstract
PURPOSE There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice. METHODS We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays. RESULTS Tumor weights in mice treated with 2 mg/kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/kg systemic dose required to achieve similar tumor control. CONCLUSION Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.
Collapse
Affiliation(s)
| | - Katie Frizzi
- Department of Pathology, University of California, San Diego, CA, USA
| | - Suna Erdem
- Moores Cancer Center, University of California, 3855 Health Sciences Dr, Rm 2336, La Jolla, San Diego, CA, 92037, USA
| | - Partha Ray
- Moores Cancer Center, University of California, 3855 Health Sciences Dr, Rm 2336, La Jolla, San Diego, CA, 92037, USA
| | - David Jaroch
- TriSalus™ Life Sciences, Inc, Westminster, CO, USA
| | - Bryan Cox
- TriSalus™ Life Sciences, Inc, Westminster, CO, USA
| | - Steven Katz
- TriSalus™ Life Sciences, Inc, Westminster, CO, USA
- Immuno-Oncology Institute, Roger Williams Medical Center, Providence, RI, USA
| | - Diego Vicente
- Moores Cancer Center, University of California, 3855 Health Sciences Dr, Rm 2336, La Jolla, San Diego, CA, 92037, USA
- Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Rebekah White
- Moores Cancer Center, University of California, 3855 Health Sciences Dr, Rm 2336, La Jolla, San Diego, CA, 92037, USA.
| |
Collapse
|
|
21
|
Sisignano M, Gribbon P, Geisslinger G. Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain. Drugs 2022; 82:357-373. [PMID: 35254645 PMCID: PMC8899787 DOI: 10.1007/s40265-022-01689-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 12/12/2022]
Abstract
Around 20% of the American population have chronic pain and estimates in other Western countries report similar numbers. This represents a major challenge for global health care systems. Additional problems for the treatment of chronic and persistent pain are the comparably low efficacy of existing therapies, the failure to translate effects observed in preclinical pain models to human patients and related setbacks in clinical trials from previous attempts to develop novel analgesics. Drug repurposing offers an alternative approach to identify novel analgesics as it can bypass various steps of classical drug development. In recent years, several approved drugs were attributed analgesic properties. Here, we review available data and discuss recent findings suggesting that the approved drugs minocycline, fingolimod, pioglitazone, nilotinib, telmisartan, and others, which were originally developed for the treatment of different pathologies, can have analgesic, antihyperalgesic, or neuroprotective effects in preclinical and clinical models of inflammatory or neuropathic pain. For our analysis, we subdivide the drugs into substances that can target neuroinflammation or substances that can act on peripheral sensory neurons, and highlight the proposed mechanisms. Finally, we discuss the merits and challenges of drug repurposing for the development of novel analgesics.
Collapse
Affiliation(s)
- Marco Sisignano
- pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany. .,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany. .,Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
| | - Philip Gribbon
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, ScreeningPort, Schnackenburgallee 114, 22525, Hamburg, Germany.,Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany
| | - Gerd Geisslinger
- pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.,Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany
| |
Collapse
|
|
22
|
Alavi N, Rezaei M, Maghami P, Fanipakdel A, Avan A. Nanocarrier System for Increasing the Therapeutic Efficacy of Oxaliplatin. Curr Cancer Drug Targets 2022; 22:361-372. [PMID: 35048809 DOI: 10.2174/1568009622666220120115140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/01/2021] [Accepted: 11/24/2021] [Indexed: 11/22/2022]
Abstract
The application of Oxaliplatin (OxPt) in different malignancies is reported to be accompanied by several side effects including neuropathy, nausea, vomiting, diarrhea, mouth sores, low blood counts, loss of appetite, etc. The passive or active targeting of different tumors can improve OxPt delivery. Considering the demand for novel systems meant to improve the OxPt efficacy and define the shortcomings, we provided an overview of different approaches regarding the delivery of OxPt. There is an extending body of data that exhibits the value of Liposomes and polymer-based drug delivery systems as the most successful systems among the OxPt drug delivery procedures. Several clinical trials have been carried out to investigate the side effects and dose-limiting toxicity of liposomal oxaliplatin such as the assessment on Safety Study of MBP-426 (Liposomal Oxaliplatin Suspension for Injection) to Treat Advanced or Metastatic Solid Tumors. In addition, several studies indicated the biocompatibility and biodegradability of this product, as well as its option for being fictionalized to derive specialized smart nanosystems for the treatment of cancer. The better delivery of OxPt with weaker side effects could be generated by the exertion of Oxaliplatin, which involves the aggregation of new particles and multifaceted nanocarriers to compose a nanocomposite with both inorganic and organic nanoparticles.
Collapse
Affiliation(s)
- Negin Alavi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Majid Rezaei
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Maghami
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Azar Fanipakdel
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
23
|
Eltayeb SA, Ciarimboli G, Beul K, Seno Di Marco G, Barz V. Role of Organic Cation Transporter 2 in Autophagy Induced by Platinum Derivatives. Int J Mol Sci 2022; 23:1090. [PMID: 35163014 PMCID: PMC8834759 DOI: 10.3390/ijms23031090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
The human organic cation transporter 2 (hOCT2) mediates renal and neuronal cellular cisplatin and oxaliplatin uptake, and therefore plays a significant role in the development of side effects associated with these chemotherapeutic drugs. Autophagy is induced by cisplatin and oxaliplatin treatment and is believed to promote cell survival under stressful conditions. We examined in vitro the role of hOCT2 on autophagy induced by cisplatin and oxaliplatin. We also explored the effect of autophagy on toxicities of these platinum derivatives. Our results indicate that autophagy, measured as LC3 II accumulation and reduction in p62 expression level, is induced in response to cisplatin and oxaliplatin in HEK293-hOCT2 but not in wild-type HEK293 cells. Furthermore, inhibition of autophagy is associated with higher toxicity of platinum derivatives, and starvation was found to offer protection against cisplatin-associated toxicity. In conclusion, activation of autophagy could be a potential strategy to protect against unwanted toxicities induced by treatment with platinum derivatives.
Collapse
Affiliation(s)
| | - Giuliano Ciarimboli
- Medicine Clinic D, Experimental Nephrology, University Hospital of Münster, 48149 Münster, Germany; (S.A.E.); (K.B.); (G.S.D.M.); (V.B.)
| | | | | | | |
Collapse
|
|
24
|
Egashira N. Pathological Mechanisms and Preventive Strategies of Oxaliplatin-Induced Peripheral Neuropathy. FRONTIERS IN PAIN RESEARCH 2021; 2:804260. [PMID: 35295491 PMCID: PMC8915546 DOI: 10.3389/fpain.2021.804260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 11/19/2021] [Indexed: 11/16/2022] Open
Abstract
Oxaliplatin, which is widely used in treating cancers such as colorectal cancer, frequently causes peripheral neuropathy. It not only significantly reduces the patient's quality of life due to physical distress but may also result in a change or discontinuation of cancer treatment. Oxaliplatin-induced peripheral neuropathy (OIPN) is classified as acute or chronic depending on the onset time of side effects; however, the prevention and treatment of OIPN has not been established. As these peripheral neuropathies are side effects that occur due to treatment, the administration of effective prophylaxis can effectively prevent their onset. Although transient relief of symptoms such as pain and numbness enable the continuation of cancer treatment, it may result in the worsening of peripheral neuropathy. Thus, understanding the pathological mechanisms of OIPN and finding better preventative measures are important. This review focuses on animal models to address these issues, clarifies the pathological mechanisms of OIPN, and summarizes various approaches to solving OIPN, including targets for preventing OIPN.
Collapse
|
|
25
|
Jilek JL, Frost KL, Jacobus KA, He W, Toth EL, Goedken M, Cherrington NJ. Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity. Acta Pharm Sin B 2021; 11:3869-3878. [PMID: 35024313 PMCID: PMC8727892 DOI: 10.1016/j.apsb.2021.05.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/09/2021] [Accepted: 04/15/2021] [Indexed: 11/26/2022] Open
Abstract
Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions. Cisplatin (CDDP) elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion. Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis (NASH), however, associated changes to substrate toxicity is unknown. To test this, a methionine- and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics, transporter expression, and toxicity. NASH rats administered CDDP (6 mg/kg, i.p.) displayed 20% less nephrotoxicity than healthy rats. Likewise, CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min, renal secretion decreased from 6.23 to 2.80 mL/min, and renal CDDP accumulation decreased by 15%, relative to healthy rats. Renal copper transporter-1 expression decreased, and organic cation transporter-2 and ATPase copper transporting protein-7b increased slightly, reducing CDDP secretion. Hepatic CDDP accumulation increased 250% in NASH rats relative to healthy rats. Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats, although no drug-related toxicity was observed. These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance, which may alter nephrotoxicity.
Collapse
Key Words
- ATP7, ATPase copper transporting protein
- CDDP, cisplatin
- CTR, copper transporter
- Cisplatin
- DDTC, diethyldithiocarbamate
- DT, drug transporter
- Drug transporter
- GFR, glomerular filtration rate
- LC–MS/MS, liquid chromatography–tandem mass spectrometry
- MATE, multidrug and toxin extrusion protein
- MCD, methionine- and choline-deficient diet
- NAFLD, nonalcoholic fatty liver disease
- NASH
- NASH, nonalcoholic steatohepatitis
- Nephrotoxicity
- Nonalcoholic steatohepatitis
- OCT, organic cation transporter
- P-gp, p-glycoprotein
- PK, pharmacokinetics
Collapse
Affiliation(s)
- Joseph L. Jilek
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA
| | - Kayla L. Frost
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA
| | - Kevyn A. Jacobus
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA
| | - Wenxi He
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA
| | - Erica L. Toth
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA
| | - Michael Goedken
- Rutgers Translational Sciences, Rutgers University, Piscataway, NJ 08901, USA
| | - Nathan J. Cherrington
- Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA,Corresponding author. Tel.: +1 520 626 0219.
| |
Collapse
|
|
26
|
Huang X, Li M, Hou S, Tian B. Role of the microbiome in systemic therapy for pancreatic ductal adenocarcinoma (Review). Int J Oncol 2021; 59:101. [PMID: 34738624 PMCID: PMC8577795 DOI: 10.3892/ijo.2021.5281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
A large body of evidence has revealed that the microbiome serves a role in all aspects of cancer, particularly cancer treatment. To date, studies investigating the relationship between the microbiome and systemic therapy for pancreatic ductal adenocarcinoma (PDAC) are lacking. PDAC is a high‑mortality malignancy (5‑year survival rate; <9% for all stages). Systemic therapy is one of the most important treatment choices for all patients; however, resistance or toxicity can affect its efficacy. Studies have supported the hypothesis that the microbiome is closely associated with the response to systemic therapy in PDAC, including the induction of drug resistance, or toxicity and therapy‑related changes in microbiota composition. The present review comprehensively summarized the role of the microbiome in systemic therapy for PDAC and the associated molecular mechanisms in an attempt to provide a novel direction for the improvement of treatment response and proposed potential directions for in‑depth research.
Collapse
Affiliation(s)
| | | | - Shengzhong Hou
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bole Tian
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| |
Collapse
|
|
27
|
Uddin ME, Talebi Z, Chen S, Jin Y, Gibson AA, Noonan AM, Cheng X, Hu S, Sparreboom A. In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors. Pharmaceutics 2021; 13:pharmaceutics13122004. [PMID: 34959286 PMCID: PMC8707461 DOI: 10.3390/pharmaceutics13122004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/16/2022] Open
Abstract
The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy.
Collapse
Affiliation(s)
- Muhammad Erfan Uddin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (Z.T.); (Y.J.); (A.A.G.)
| | - Zahra Talebi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (Z.T.); (Y.J.); (A.A.G.)
| | - Sijie Chen
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.C.); (X.C.)
| | - Yan Jin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (Z.T.); (Y.J.); (A.A.G.)
| | - Alice A. Gibson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (Z.T.); (Y.J.); (A.A.G.)
| | - Anne M. Noonan
- Department of Internal Medicine, Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA;
| | - Xiaolin Cheng
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.C.); (X.C.)
| | - Shuiying Hu
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (M.E.U.); (Z.T.); (Y.J.); (A.A.G.)
- Correspondence:
| |
Collapse
|
|
28
|
Hu X, Jiang Z, Teng L, Yang H, Hong D, Zheng D, Zhao Q. Platinum-Induced Peripheral Neuropathy (PIPN): ROS-Related Mechanism, Therapeutic Agents, and Nanosystems. Front Mol Biosci 2021; 8:770808. [PMID: 34901160 PMCID: PMC8652200 DOI: 10.3389/fmolb.2021.770808] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
Platinum (Pt) drugs (e.g., oxaliplatin, cisplatin) are applied in the clinic worldwide for the treatment of various cancers. However, platinum-induced peripheral neuropathy (PIPN) caused by the accumulation of Pt in the peripheral nervous system limits the clinical application, whose prevention and treatment are still a huge challenge. To date, Pt-induced reactive oxygen species (ROS) generation has been studied as one of the primary mechanisms of PIPN, whose downregulation would be feasible to relieve PIPN. This review will discuss ROS-related PIPN mechanisms including Pt accumulation in the dorsal root ganglia (DRG), ROS generation, and cellular regulation. Based on them, some antioxidant therapeutic drugs will be summarized in detail to alleviate the Pt-induced ROS overproduction. More importantly, we focus on the cutting-edge nanotechnology in view of ROS-related PIPN mechanisms and will discuss the rational fabrication of tailor-made nanosystems for efficiently preventing and treating PIPN. Last, the future prospects and potential breakthroughs of these anti-ROS agents and nanosystems will be briefly discussed.
Collapse
Affiliation(s)
- Xi Hu
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhijie Jiang
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Longyu Teng
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongyu Yang
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongsheng Hong
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongsheng Zheng
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingwei Zhao
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
29
|
Ciarimboli G. Anticancer Platinum Drugs Update. Biomolecules 2021; 11:biom11111637. [PMID: 34827636 PMCID: PMC8615753 DOI: 10.3390/biom11111637] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/03/2021] [Indexed: 12/15/2022] Open
Affiliation(s)
- Giuliano Ciarimboli
- Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, 48149 Münster, Germany
| |
Collapse
|
|
30
|
Yang Y, Zhao B, Gao X, Sun J, Ye J, Li J, Cao P. Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:331. [PMID: 34686205 PMCID: PMC8532307 DOI: 10.1186/s13046-021-02141-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/12/2021] [Indexed: 12/17/2022]
Abstract
Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a severe clinical problem and potentially permanent side effect of cancer treatment. For the management of OIPN, accurate diagnosis and understanding of significant risk factors including genetic vulnerability are essential to improve knowledge regarding the prevalence and incidence of OIPN as well as enhance strategies for the prevention and treatment of OIPN. The molecular mechanisms underlying OIPN are complex, with multi-targets and various cells causing neuropathy. Furthermore, mechanisms of OIPN can reinforce each other, and combination therapies may be required for effective management. However, despite intense investigation in preclinical and clinical studies, no preventive therapies have shown significant clinical efficacy, and the established treatment for painful OIPN is limited. Duloxetine is the only agent currently recommended by the American Society of Clinical Oncology. The present article summarizes the most recent advances in the field of studies on OIPN, the overview of the clinical syndrome, molecular basis, therapy development, and outlook of future drug candidates. Importantly, closer links between clinical pain management teams and oncology will advance the effectiveness of OIPN treatment, and the continued close collaboration between preclinical and clinical research will facilitate the development of novel prevention and treatments for OIPN.
Collapse
Affiliation(s)
- Yang Yang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100#, Hongshan Road, Nanjing, 210028, Jiangsu, China. .,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. .,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. .,Yangtze River Pharmaceutical Group, Taizhou, 225321, China.
| | - Bing Zhao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100#, Hongshan Road, Nanjing, 210028, Jiangsu, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xuejiao Gao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100#, Hongshan Road, Nanjing, 210028, Jiangsu, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jinbing Sun
- Changshu No.1 People's Hospital Affiliated to Soochow University, Changshu, 215500, China
| | - Juan Ye
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100#, Hongshan Road, Nanjing, 210028, Jiangsu, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jun Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P.R. China
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100#, Hongshan Road, Nanjing, 210028, Jiangsu, China. .,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. .,Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang, 212002, Jiangsu, China.
| |
Collapse
|
|
31
|
Sun D, Chen Q, Gai Z, Zhang F, Yang X, Hu W, Chen C, Yang G, Hörmann S, Kullak-Ublick GA, Visentin M. The Role of the Carnitine/Organic Cation Transporter Novel 2 in the Clinical Outcome of Patients With Locally Advanced Esophageal Carcinoma Treated With Oxaliplatin. Front Pharmacol 2021; 12:684545. [PMID: 34603016 PMCID: PMC8481660 DOI: 10.3389/fphar.2021.684545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/18/2021] [Indexed: 01/25/2023] Open
Abstract
Esophageal cancer is the ninth most common malignancy worldwide, ranking sixth in mortality. Platinum-based chemotherapy is commonly used for treating locally advanced esophageal cancer, yet it is ineffective in a large portion of patients. There is a need for reliable molecular markers with direct clinical application for a prospective selection of patients who can benefit from chemotherapy and patients in whom toxicity is likely to outweigh the benefit. The cytotoxic activity of platinum derivatives largely depends on the uptake and accumulation into cells, primarily by organic cation transporters (OCTs). The aim of the study was to investigate the impact of OCT expression on the clinical outcome of patients with esophageal cancer treated with oxaliplatin. Twenty patients with esophageal squamous cell carcinoma (SCC) were prospectively enrolled and surgical specimens used for screening OCT expression level by western blotting and/or immunostaining, and for culture of cancer cells. Sixty-seven patients with SCC who received oxaliplatin and for whom follow-up was available were retrospectively assessed for organic cation/carnitine transporter 2 (OCTN2) expression by real time RT-PCR and immunostaining. OCTN2 staining was also performed in 22 esophageal adenocarcinomas. OCTN2 function in patient-derived cancer cells was evaluated by assessing L-carnitine uptake and sensitivity to oxaliplatin. The impact of OCTN2 on oxaliplatin activity was also assessed in HEK293 cells overexpressing OCTN2. OCTN2 expression was higher in tumor than in normal tissues. In patient-derived cancer cells and HEK293 cells, the expression of OCTN2 sensitized to oxaliplatin. Patients treated with oxaliplatin who had high OCTN2 level in the tumor tissue had a reduced risk of recurrence and a longer survival time than those with low expression of OCTN2 in tumor tissue. In conclusion, OCTN2 is expressed in esophageal cancer and it is likely to contribute to the accumulation and cytotoxic activity of oxaliplatin in patients with esophageal carcinoma treated with oxaliplatin.
Collapse
Affiliation(s)
- Dongfeng Sun
- Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Emergency Medicine, Shandong Lung Cancer Institute, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Qingfa Chen
- The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, China
| | - Zhibo Gai
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Fengxia Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Emergency Medicine, Shandong Lung Cancer Institute, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Xiaoqing Yang
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Wensi Hu
- Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Emergency Medicine, Shandong Lung Cancer Institute, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Chengyu Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Emergency Medicine, Shandong Lung Cancer Institute, Shandong Institute of Respiratory Diseases, Jinan, China
| | - Guangjie Yang
- Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Severin Hörmann
- Department of Pathology and Molecular Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michele Visentin
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| |
Collapse
|
|
32
|
Pasquariello KZ, Dey JM, Sprowl JA. Current Understanding of Membrane Transporters as Regulators or Targets for Cisplatin-Induced Hearing Loss. Mol Pharmacol 2021; 100:348-355. [PMID: 34330821 PMCID: PMC8626641 DOI: 10.1124/molpharm.121.000274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/22/2021] [Indexed: 11/22/2022] Open
Abstract
Cisplatin is a platinum-based drug, which remains among the most efficacious anticancer treatment options. Unfortunately, use of cisplatin is hindered by dose-limiting toxicities, including irreversible hearing loss, which can grossly affect patient quality of life. Cisplatin-induced ototoxicity is the result of cochlear hair cell damage through a mechanism that is poorly understood. However, cisplatin cytotoxicity is reliant on intracellular accumulation, a process that is largely dependent on the presence of particular membrane transporters. This review will provide an update on our current understanding of the various transporters known to be involved in the disposition and cytotoxicity of platinum drugs or their metabolites, as well as their role in mediating cisplatin-induced hearing loss. We also provide a summary of the successes and opportunities in therapeutically targeting membrane transporters to alleviate platinum-induced hearing loss. Moreover, we describe how this approach could be used to reduce the severity or onset of other adverse events associated with exposure to various forms of platinum drugs, without diminishing antitumor efficacy. SIGNIFICANCE STATEMENT: Cisplatin-induced hearing loss is a dose-limiting and irreversible adverse event with no current preventative or curative treatment measures. Pharmacological targeting of membrane transporters that regulate platinum uptake into cochlear hair cells, if conducted appropriately, may alleviate this devastating side effect and could be applied to alleviate other platinum-induced toxicities.
Collapse
Affiliation(s)
- Kyle Z Pasquariello
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York
| | - Jason M Dey
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York
| | - Jason A Sprowl
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York
| |
Collapse
|
|
33
|
Gu Z, Wei G, Zhu L, Zhu L, Hu J, Li Q, Cai G, Lu H, Liu M, Chen C, Ji Y, Li G, Huo J. Preventive Efficacy and Safety of Yiqi-Wenjing-Fang Granules on Oxaliplatin-Induced Peripheral Neuropathy: A Protocol for a Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:5551568. [PMID: 34630609 PMCID: PMC8494586 DOI: 10.1155/2021/5551568] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 09/01/2021] [Accepted: 09/20/2021] [Indexed: 11/18/2022]
Abstract
Background. Oxaliplatin-induced peripheral neuropathy (OIPN) is one of the most common side effects of oxaliplatin, which can cause reduction and cessation of oxaliplatin-based chemotherapy and significantly affect patients' quality of life. However, no drug has got recognition to prevent or treat OIPN. Yiqi-Wenjing-Fang (YWF) is a joint name of Chinese medicine prescriptions with similar effects of tonifying qi and warming meridians, represented by Huangqi Guizhi Wuwu decoction (HGWD) and Danggui Sini decoction (DSD), both from "Treatise on Cold Pathogenic and Miscellaneous Diseases." YWF granules, including HGWD granules and DSD granules, have been, respectively, demonstrated to be effective in preventing OIPN in previous small-sample observations. The purpose of this study is to enlarge the sample size for further evaluation of the preventive efficacy and safety of YWF granules on OIPN. Methods and Analysis. This study is a randomized, double-blind, placebo-controlled, and multicenter clinical trial. 360 postoperative patients with stage IIa-IIIc colorectal cancer will be randomly assigned into placebo-control group, intervention group I, and intervention group II, taking the mimetic granules of YWF as placebo, HGWD granules and DSD granules, respectively. All subjects will receive oxaliplatin-based chemotherapy regimen at the same time. EORTC QLQ-CIPN20 will be used to assess the degree of OIPN as the primary outcome measure. The grades of OIPN, quality of life, chemotherapeutic efficacy, and the number of completed chemotherapy cycles are selected as the secondary outcome measures. Discussion. Based on the condition of no recognized effective drugs in preventing OIPN, evidence-based medical study will be conducted for seeking a breakthrough in the field of Chinese herb medicine. This protocol could provide reliable and systemic research basis about the efficacy of YWF granules and the differentiation of two classical prescriptions of YWF on preventing OIPN objectively. Trial Registration. This study was registered at ClinicalTrials.gov on 26 December 2020 (ID: https://clinicaltrials.gov/ct2/show/NCT04690283).
Collapse
Affiliation(s)
- Zhancheng Gu
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Guoli Wei
- Department of Oncology, Jiangsu Provincial Hospital of Integrated Chinese and Western Medicine, Nanjing 210046, China
| | - Liangjun Zhu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing 210009, China
| | - Lingjun Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jing Hu
- Department of Medical Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Qi Li
- Department of Oncology, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Hong Lu
- Department of Chemotherapy, Changshu No. 1 People's Hospital, Chuzhou 239001, China
| | - Min Liu
- Department of Oncology, Suzhou Hospital of Traditional Chinese Medicine, Suzhou 215002, China
| | - Chen Chen
- Department of Oncology, Yancheng Hospital of Traditional Chinese Medicine, Yancheng 224005, China
| | - Yi Ji
- Department of Oncology, Jiangsu Provincial Hospital of Integrated Chinese and Western Medicine, Nanjing 210046, China
| | - Guochun Li
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Jiege Huo
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China
- Department of Oncology, Jiangsu Provincial Hospital of Integrated Chinese and Western Medicine, Nanjing 210046, China
| |
Collapse
|
|
34
|
Kell DB. The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes. Molecules 2021; 26:5629. [PMID: 34577099 PMCID: PMC8470029 DOI: 10.3390/molecules26185629] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/03/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport "phospholipid bilayer transport is negligible".
Collapse
Affiliation(s)
- Douglas B. Kell
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St, Liverpool L69 7ZB, UK;
- Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet, 2800 Kgs Lyngby, Denmark
- Mellizyme Biotechnology Ltd., IC1, Liverpool Science Park, Mount Pleasant, Liverpool L3 5TF, UK
| |
Collapse
|
|
35
|
Garrison DA, Jin Y, Uddin ME, Sparreboom A, Baker SD. Development, validation, and application of an LC-MS/MS method for the determination of the AXL/FLT3 inhibitor gilteritinib in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1179:122882. [PMID: 34365291 DOI: 10.1016/j.jchromb.2021.122882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 12/27/2022]
Abstract
A simple, fast and precise LC-MS/MS method for the quantitation of the tyrosine kinase inhibitor gilteritinib was developed and validated for micro-volumes of mouse plasma. The assay procedure involved a one-step extraction of gilteritinib and the internal standard [2H5]-gilteritinib with acetonitrile. An Accucore aQ column was used to separate analytes using a gradient elution delivered at a flow rate of 0.4 mL/min, and a total run time of 2.5 min. Validation studies with quality control samples processed on consecutive days revealed that values for intra-day and inter-day precision were <7.04%, with an accuracy of 101-108%. Linear responses were observed over the entire calibration curve range (up to 500 ng/mL), and the lower limit of quantification was 5 ng/mL. The developed method was successfully used to examine the pharmacokinetics of oral gilteritinib in wild-type mice and mice lacking the organic cation transporters OCT1, OCT2, and MATE1 to further understand mechanisms contributing to drug-drug interactions and causes of inter-individual pharmacokinetic variability.
Collapse
Affiliation(s)
- Dominique A Garrison
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Yan Jin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Muhammad Erfan Uddin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Sharyn D Baker
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
| |
Collapse
|
|
36
|
Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment. Int J Mol Sci 2021; 22:ijms22158199. [PMID: 34360968 PMCID: PMC8347825 DOI: 10.3390/ijms22158199] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.
Collapse
|
|
37
|
Bouchenaki H, Danigo A, Bernard A, Bessaguet F, Richard L, Sturtz F, Balayssac D, Magy L, Demiot C. Ramipril Alleviates Oxaliplatin-Induced Acute Pain Syndrome in Mice. Front Pharmacol 2021; 12:712442. [PMID: 34349658 PMCID: PMC8326755 DOI: 10.3389/fphar.2021.712442] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 06/25/2021] [Indexed: 02/05/2023] Open
Abstract
Oxaliplatin is a key drug for colorectal cancer that causes OXP-induced peripheral neuropathy, a dose-limiting effect characterized by cold and tactile hyperesthesia. The relationship between the sensory nervous system and modulation of the renin-angiotensin system has been described, focusing on pain and neurodegeneration in several animal models. We assessed the effect of the RAS modulator, ramipril, an angiotensin converting-enzyme inhibitor in a mouse model of OXP-induced acute pain syndrome. OXP was administered in Swiss mice at a cumulative dose of 15 mg/kg (3 x 5 mg/kg/3 days, i.p.). RAM was administered i.p. every day from 24 h before the first OXP injection until the end of the experiments. We evaluated OIAS development and treatment effects by sensorimotor tests, intraepidermal nerve fiber and dorsal root ganglia-neuron immunohistochemical analyses, and sciatic nerve ultrastructural analysis. OXP-treated mice showed tactile allodynia and cold hypersensitivity, without motor impairment and evidence of nerve degeneration. RAM prevented cold sensitivity and improved recovery of normal tactile sensitivity in OXP-treated mice. Our finding that RAM alleviates OXP-induced pain is a step towards evaluating its therapeutic potential in patients receiving OXP treatment.
Collapse
Affiliation(s)
- Hichem Bouchenaki
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
| | - Aurore Danigo
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
| | - Amandine Bernard
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
| | - Flavien Bessaguet
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
| | - Laurence Richard
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France.,Department of Neurology, Reference Center for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges, France
| | - Franck Sturtz
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
| | - David Balayssac
- Neuro-Dol, UMR1107 INSERM, University of Clermont Auvergne, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Laurent Magy
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France.,Department of Neurology, Reference Center for Rare Peripheral Neuropathies, University Hospital of Limoges, Limoges, France
| | - Claire Demiot
- EA 6309 - Myelin Maintenance and Peripheral Neuropathy, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
| |
Collapse
|
|
38
|
Yi Y, Li L, Song F, Li P, Chen M, Ni S, Zhang H, Zhou H, Zeng S, Jiang H. L-tetrahydropalmatine reduces oxaliplatin accumulation in the dorsal root ganglion and mitochondria through selectively inhibiting the transporter-mediated uptake thereby attenuates peripheral neurotoxicity. Toxicology 2021; 459:152853. [PMID: 34252480 DOI: 10.1016/j.tox.2021.152853] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/02/2021] [Accepted: 07/08/2021] [Indexed: 12/26/2022]
Abstract
Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 μM) reduced OXA (40 μM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 μM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 μM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.
Collapse
Affiliation(s)
- Yaodong Yi
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Liping Li
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Feifeng Song
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Ping Li
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Mingyang Chen
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Shixin Ni
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Hengbin Zhang
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Hui Zhou
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Su Zeng
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Huidi Jiang
- Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
| |
Collapse
|
|
39
|
Boztepe T, Castro GR, León IE. Lipid, polymeric, inorganic-based drug delivery applications for platinum-based anticancer drugs. Int J Pharm 2021; 605:120788. [PMID: 34116182 DOI: 10.1016/j.ijpharm.2021.120788] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 06/02/2021] [Accepted: 06/05/2021] [Indexed: 12/13/2022]
Abstract
The three main FDA-approved platinum drugs in chemotherapy such as carboplatin, cisplatin, and oxaliplatin are extensively applied in cancer treatments. Although the clinical applications of platinum-based drugs are extremely effective, their toxicity profile restricts their extensive application. Therefore, recent studies focus on developing new platinum drug formulations, expanding the therapeutic aspect. In this sense, recent advances in the development of novel drug delivery carriers will help with the increase of drug stability and biodisponibility, concomitantly with the reduction of drug efflux and undesirable secondary toxic effects of platinum compounds. The present review describes the state of the art of platinum drugs with their biological effects, pre- and clinical studies, and novel drug delivery nanodevices based on lipids, polymers, and inorganic.
Collapse
Affiliation(s)
- Tugce Boztepe
- Laboratorio de Nanobiomateriales, CINDEFI - Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata-CONICET (CCT La Plata), Calle 47 y 115, B1900AJL La Plata, Argentina
| | - Guillermo R Castro
- Laboratorio de Nanobiomateriales, CINDEFI - Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata-CONICET (CCT La Plata), Calle 47 y 115, B1900AJL La Plata, Argentina; Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC), Partner Laboratory of the Max Planck Institute for Biophysical Chemistry (MPIbpC, MPG), Centro de Estudios Interdisciplinarios (CEI), Universidad Nacional de Rosario, Maipú 1065, S2000 Rosario, Santa Fe, Argentina.
| | - Ignacio E León
- Centro de Química Inorgánica, CEQUINOR (CONICET-UNLP), Bv. 120 1465, La Plata, Argentina.
| |
Collapse
|
|
40
|
Kuo MT, Huang YF, Chou CY, Chen HHW. Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy. Pharmaceuticals (Basel) 2021; 14:ph14060549. [PMID: 34201235 PMCID: PMC8227247 DOI: 10.3390/ph14060549] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/05/2021] [Accepted: 06/07/2021] [Indexed: 12/18/2022] Open
Abstract
The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.
Collapse
Affiliation(s)
- Macus Tien Kuo
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Yu-Fang Huang
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
| | - Cheng-Yang Chou
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
- Correspondence: (C.-Y.C.); (H.H.W.C.)
| | - Helen H. W. Chen
- Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan 701, Taiwan
- Correspondence: (C.-Y.C.); (H.H.W.C.)
| |
Collapse
|
|
41
|
Lazić D, Scheurer A, Ćoćić D, Milovanović J, Arsenijević A, Stojanović B, Arsenijević N, Milovanović M, Rilak Simović A. A new bis-pyrazolylpyridine ruthenium(III) complex as a potential anticancer drug: in vitro and in vivo activity in murine colon cancer. Dalton Trans 2021; 50:7686-7704. [PMID: 33982702 DOI: 10.1039/d1dt00185j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
We synthesized and characterized the ruthenium(iii) pincer-type complex [RuCl3(H2Lt-Bu] (H2Lt-Bu = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine, 1) by elemental analysis, IR and UV-Vis spectroscopy, and the mass spectrometry (MS) method ESI Q-TOF. For comparison reasons, we also studied ruthenium(iii) terpyridine complexes of the general formula [Ru(N-N-N)Cl3], where N-N-N = 4'-chloro-terpyridine (Cl-tpy; 2) or 4'-chlorophenyl-terpyridine (Cl-Ph-tpy; 3). A kinetic study of the substitution reactions of 1-3 with biomolecules showed that the rate constants depend on the properties of the spectator ligand and the nature of the entering nucleophile. The DNA/HSA binding study showed that in comparison to complex 1 (bis-pyrazolylpyridine), the other two (2 and 3) terpyridine complexes had a slightly better binding affinity to calf thymus DNA (CT DNA), while in the case of human serum albumin (HSA), complex 1 exhibited the strongest quenching ability. We demonstrated that 1 possesses significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells and in vivo antitumor activity in murine heterotopic colon carcinoma. Complex 1 induced G0/G1 cell cycle arrest and apoptotic death in CT26 cells. Additionally, 1 showed antiproliferative activity, as evaluated by the detection of the expression levels of the Ki67 protein. Furthermore, the in vivo results showed that 1 reduced primary tumour growth and the number and growth of lung and liver metastases, significantly prolonging the treated mice's survival rate. This study highlighted that 1 does not show hepato- and nephrotoxicity. Our data demonstrated the considerable antitumor activity of the ruthenium(iii) pincer complex against CT26 tumour cells and implicated further investigations of its role as a potential chemotherapeutic agent for colon carcinoma.
Collapse
Affiliation(s)
- Dejan Lazić
- Department of Surgery, Faculty of Medical Sciences, University of Kraujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
| | - Andreas Scheurer
- Inorganic Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Dušan Ćoćić
- University of Kragujevac, Faculty of Science, Radoja Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia
| | - Jelena Milovanović
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia. and Department of Histology, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Aleksandar Arsenijević
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
| | - Bojana Stojanović
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia. and Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Nebojša Arsenijević
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
| | - Marija Milovanović
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
| | - Ana Rilak Simović
- University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Natural Sciences, Jovana Cvijića bb, 34000 Kragujevac, Serbia.
| |
Collapse
|
|
42
|
Schorn S, Dicke AK, Neugebauer U, Schröter R, Friedrich M, Reuter S, Ciarimboli G. Expression and Function of Organic Cation Transporter 2 in Pancreas. Front Cell Dev Biol 2021; 9:688885. [PMID: 34124075 PMCID: PMC8195675 DOI: 10.3389/fcell.2021.688885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 04/30/2021] [Indexed: 01/11/2023] Open
Abstract
Organic cation transporters (OCT) play an important role in mediating cellular uptake of several pharmaceuticals, such as the antidiabetic drug metformin and the platinum-derived chemotherapeutics. Since these drugs can also affect the pancreas, here it was investigated whether these transporters are expressed in this organ. An interaction between OCT2 and the glucose transporter 2 (GLUT2), which is expressed with important functional consequences in the kidneys and in the pancreas, has already been demonstrated elsewhere. Therefore, here it was further investigated whether the two proteins have a functional relationship. It was demonstrated that OCT2 is expressed in pancreas, probably in β cells of Langerhans islets, together with GLUT2. However, a co-localization was only evident in a cell-line model of rat pancreatic β cells under incubation with high glucose concentration. High glucose stimulated OCT2 expression and activity. On the other side, studies conducted in human embryonic kidney cells stably expressing OCT2, showed that overexpression of GLUT2 decreased OCT2 activity. Unfortunately, pull-down experiments aimed to confirm a physical OCT2/GLUT2 interaction were not successful. Renal glucose excretion was reduced in mice with genetic deletion of OCT2. Nonetheless, in these mice no regulation of known kidney glucose transporters was measured. Therefore, it may be speculated that OCT2 may influence cellular trafficking of GLUT2, without changing its amount. OCT2 may play a role in drug uptake of the pancreas, and its activity may be regulated by glucose and GLUT2. Vice versa, GLUT2 activity may be regulated through an interaction with OCT2.
Collapse
Affiliation(s)
- Sandra Schorn
- Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany
| | - Ann-Kristin Dicke
- Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany
| | - Ute Neugebauer
- Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany
| | - Rita Schröter
- Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany
| | - Maren Friedrich
- Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany
| | - Stefan Reuter
- Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany
| | - Giuliano Ciarimboli
- Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany
| |
Collapse
|
|
43
|
Sweet DH. Organic Cation Transporter Expression and Function in the CNS. Handb Exp Pharmacol 2021; 266:41-80. [PMID: 33963461 DOI: 10.1007/164_2021_463] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) represent major control checkpoints protecting the CNS, by exerting selective control over the movement of organic cations and anions into and out of the CNS compartment. In addition, multiple CNS cell types, e.g., astrocytes, ependymal cells, microglia, contribute to processes that maintain the status quo of the CNS milieu. To fulfill their roles, these barriers and cell types express a multitude of transporter proteins from dozens of different transporter families. Fundamental advances over the past few decades in our knowledge of transporter substrates, expression profiles, and consequences of loss of function are beginning to change basic theories regarding the contribution of various cell types and clearance networks to coordinated neuronal signaling, complex organismal behaviors, and overall CNS homeostasis. In particular, transporters belonging to the Solute Carrier (SLC) superfamily are emerging as major contributors, including the SLC22 organic cation/anion/zwitterion family of transporters (includes OCT1-3 and OCTN1-3), the SLC29 facilitative nucleoside family of transporters (includes PMAT), and the SLC47 multidrug and toxin extrusion family of transporters (includes MATE1-2). These transporters are known to interact with neurotransmitters, antidepressant and anxiolytic agents, and drugs of abuse. Clarifying their contributions to the underlying mechanisms regulating CNS permeation and clearance, as well as the health status of astrocyte, microglial and neuronal cell populations, will drive new levels of understanding as to maintenance of the CNS milieu and approaches to new therapeutics and therapeutic strategies in the treatment of CNS disorders. This chapter highlights organic cation transporters belonging to the SLC superfamily known to be expressed in the CNS, providing an overview of their identification, mechanism of action, CNS expression profile, interaction with neurotransmitters and antidepressant/antipsychotic drugs, and results from behavioral studies conducted in loss of function models (knockout/knockdown).
Collapse
Affiliation(s)
- Douglas H Sweet
- Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
| |
Collapse
|
|
44
|
Wang M, Chen W, Chen J, Yuan S, Hu J, Han B, Huang Y, Zhou W. Abnormal saccharides affecting cancer multi-drug resistance (MDR) and the reversal strategies. Eur J Med Chem 2021; 220:113487. [PMID: 33933752 DOI: 10.1016/j.ejmech.2021.113487] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/24/2021] [Accepted: 04/15/2021] [Indexed: 02/07/2023]
Abstract
Clinically, chemotherapy is the mainstay in the treatment of multiple cancers. However, highly adaptable and activated survival signaling pathways of cancer cells readily emerge after long exposure to chemotherapeutics drugs, resulting in multi-drug resistance (MDR) and treatment failure. Recently, growing evidences indicate that the molecular action mechanisms of cancer MDR are closely associated with abnormalities in saccharides. In this review, saccharides affecting cancer MDR development are elaborated and analyzed in terms of aberrant aerobic glycolysis and its related enzymes, abnormal glycan structures and their associated enzymes, and glycoproteins. The reversal strategies including depletion of ATP, circumventing the original MDR pathway, activation by or inhibition of sugar-related enzymes, combination therapy with traditional cytotoxic agents, and direct modification on the sugar moiety, are ultimately proposed. It follows that abnormal saccharides have a significant effect on cancer MDR development, providing a new perspective for overcoming MDR and improving the outcome of chemotherapy.
Collapse
Affiliation(s)
- Meizhu Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China
| | - Wenming Chen
- Department of Pharmaceutical Production Center, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China
| | - Jiansheng Chen
- College of Horticulture, South China Agricultural University, 483, Wushan Rd, Guangzhou, Guangdong province, 510642, China
| | - Sisi Yuan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China
| | - Jiliang Hu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China
| | - Bangxing Han
- Department of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, Anhui, China; Anhui Engineering Laboratory for Conservation and Sustainable Utilization of Traditional Chinese Medicine Resources, West Anhui University, Lu'an, Anhui, China
| | - Yahui Huang
- College of Horticulture, South China Agricultural University, 483, Wushan Rd, Guangzhou, Guangdong province, 510642, China.
| | - Wen Zhou
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
| |
Collapse
|
|
45
|
Uddin ME, Garrison DA, Kim K, Jin Y, Eisenmann ED, Huang KM, Gibson AA, Hu Z, Sparreboom A, Hu S. Influence of YES1 Kinase and Tyrosine Phosphorylation on the Activity of OCT1. Front Pharmacol 2021; 12:644342. [PMID: 33790797 PMCID: PMC8006202 DOI: 10.3389/fphar.2021.644342] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/02/2021] [Indexed: 01/11/2023] Open
Abstract
Organic cation transporter 1 (OCT1) is a transporter that regulates the hepatic uptake and subsequent elimination of diverse cationic compounds. Although OCT1 has been involved in drug-drug interactions and causes pharmacokinetic variability of many prescription drugs, details of the molecular mechanisms that regulate the activity of OCT1 remain incompletely understood. Based on an unbiased phospho-proteomics screen, we identified OCT1 as a tyrosine-phosphorylated transporter, and functional validation studies using genetic and pharmacological approaches revealed that OCT1 is highly sensitive to small molecules that target the protein kinase YES1, such as dasatinib. In addition, we found that dasatinib can inhibit hepatic OCT1 function in mice as evidenced from its ability to modulate levels of isobutyryl L-carnitine, a hepatic OCT1 biomarker identified from a targeted metabolomics analysis. These findings provide novel insight into the post-translational regulation of OCT1 and suggest that caution is warranted with polypharmacy regimes involving the combined use of OCT1 substrates and kinase inhibitors that target YES1.
Collapse
Affiliation(s)
- Muhammad Erfan Uddin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Dominique A Garrison
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Kyeongmin Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Yan Jin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Eric D Eisenmann
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Kevin M Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Alice A Gibson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Zeping Hu
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| |
Collapse
|
|
46
|
Zhang Y, Li C, Qin Y, Cepparulo P, Millman M, Chopp M, Kemper A, Szalad A, Lu X, Wang L, Zhang ZG. Small extracellular vesicles ameliorate peripheral neuropathy and enhance chemotherapy of oxaliplatin on ovarian cancer. J Extracell Vesicles 2021; 10:e12073. [PMID: 33728031 PMCID: PMC7931803 DOI: 10.1002/jev2.12073] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 01/07/2021] [Accepted: 02/13/2021] [Indexed: 12/17/2022] Open
Abstract
There are no effective treatments for chemotherapy induced peripheral neuropathy (CIPN). Small extracellular vesicles (sEVs) facilitate intercellular communication and mediate nerve function and tumour progression. We found that the treatment of mice bearing ovarian tumour with sEVs derived from cerebral endothelial cells (CEC-sEVs) in combination with a chemo-drug, oxaliplatin, robustly reduced oxaliplatin-induced CIPN by decreasing oxaliplatin-damaged myelination and nerve fibres of the sciatic nerve and significantly amplified chemotherapy of oxaliplatin by reducing tumour size. The combination therapy substantially increased a set of sEV cargo-enriched miRNAs, but significantly reduced oxaliplatin-increased proteins in the sciatic nerve and tumour tissues. Bioinformatics analysis revealed the altered miRNAs and proteins formed two distinct networks that regulate neuropathy and tumour growth, respectively. Intravenously administered CEC-sEVs were internalized by axons of the sciatic nerve and cancer cells. Reduction of CEC-sEV cargo miRNAs abolished the effects of CEC-sEVs on oxaliplatin-inhibited axonal growth and on amplification of the anti-cancer effect in ovarian cancer cells, suggesting that alterations in the networks of miRNAs and proteins in recipient cells contribute to the therapeutic effect of CEC-sEVs on CIPN. Together, the present study demonstrates that CEC-sEVs suppressed CIPN and enhanced chemotherapy of oxaliplatin in the mouse bearing ovarian tumour.
Collapse
Affiliation(s)
- Yi Zhang
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Chao Li
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Yi Qin
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | | | | | - Michael Chopp
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
- Department of PhysicsOakland UniversityRochesterMichiganUSA
| | - Amy Kemper
- Department of PathologyHenry Ford Health SystemDetroitMichiganUSA
| | - Alexandra Szalad
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Xuerong Lu
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Lei Wang
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| | - Zheng Gang Zhang
- Department of NeurologyHenry Ford Health SystemDetroitMichiganUSA
| |
Collapse
|
|
47
|
Wei G, Gu Z, Gu J, Yu J, Huang X, Qin F, Li L, Ding R, Huo J. Platinum accumulation in oxaliplatin-induced peripheral neuropathy. J Peripher Nerv Syst 2021; 26:35-42. [PMID: 33462873 PMCID: PMC7986112 DOI: 10.1111/jns.12432] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022]
Abstract
Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high-affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.
Collapse
Affiliation(s)
- Guoli Wei
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Zhancheng Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Yu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Xiaofei Huang
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Fengxia Qin
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Lingchang Li
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Rong Ding
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| |
Collapse
|
|
48
|
Staurengo-Ferrari L, Green PG, Araldi D, Ferrari LF, Miaskowski C, Levine JD. Sexual dimorphism in the contribution of neuroendocrine stress axes to oxaliplatin-induced painful peripheral neuropathy. Pain 2021; 162:907-918. [PMID: 32947545 PMCID: PMC7886966 DOI: 10.1097/j.pain.0000000000002073] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 08/24/2020] [Indexed: 01/05/2023]
Abstract
ABSTRACT Although clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide targeting β₂-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. By contrast, glucocorticoid receptor antisense oligodeoxynucleotide prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone, and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also, a risk factor for CIPN, early-life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding) and stress-resilient (produced by neonatal handling) phenotypes in adults. Although neonatal limited bedding significantly enhanced CIPN only in female adults, neonatal handling significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the 2 major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.
Collapse
Affiliation(s)
- Larissa Staurengo-Ferrari
- Departments of Medicine and Oral & Maxillofacial Surgery, Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Paul G. Green
- Departments of Preventative & Restorative Dental Sciences and Oral & Maxillofacial Surgery, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Dionéia Araldi
- Departments of Medicine and Oral & Maxillofacial Surgery, Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Luiz F. Ferrari
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Current address: Department of Anesthesiology, University of Utah, 30 N Medical Dr. RM 3C4444, Salt Lake City, UT 84132
| | - Christine Miaskowski
- Departments of Physiological Nursing and Anesthesia, UCSF Pain and Addiction Research Center, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Jon D. Levine
- Departments of Medicine and Oral & Maxillofacial Surgery, Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| |
Collapse
|
|
49
|
The Role of Nucleotide Excision Repair in Cisplatin-Induced Peripheral Neuropathy: Mechanism, Prevention, and Treatment. Int J Mol Sci 2021; 22:ijms22041975. [PMID: 33671279 PMCID: PMC7921932 DOI: 10.3390/ijms22041975] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Platinum-based chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting effects of cancer treatment and results in dose reduction and discontinuation of life-saving chemotherapy. Its debilitating effects are often permanent and lead to lifelong impairment of quality of life in cancer patients. While the mechanisms underlying the toxicity are not yet fully defined, dorsal root ganglia sensory neurons play an integral role in symptom development. DNA-platinum adducts accumulate in these cells and inhibit normal cellular function. Nucleotide excision repair (NER) is integral to the repair of platinum adducts, and proteins involved in its mechanism serve as potential targets for future therapeutics. This review aims to highlight NER’s role in cisplatin-induced peripheral neuropathy, summarize current clinical approaches to the toxicity, and discuss future perspectives for the prevention and treatment of CIPN.
Collapse
|
|
50
|
Huang KM, Leblanc AF, Uddin ME, Kim JY, Chen M, Eisenmann ED, Gibson AA, Li Y, Hong KW, DiGiacomo D, Xia SH, Alberti P, Chiorazzi A, Housley SN, Cope TC, Sprowl JA, Wang J, Loprinzi CL, Noonan A, Lustberg MB, Cavaletti G, Pabla N, Hu S, Sparreboom A. Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice. J Clin Invest 2021; 130:4601-4606. [PMID: 32484793 DOI: 10.1172/jci136796] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/15/2020] [Indexed: 12/31/2022] Open
Abstract
Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.
Collapse
Affiliation(s)
- Kevin M Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Alix F Leblanc
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Muhammad Erfan Uddin
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Ji Young Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Mingqing Chen
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Eric D Eisenmann
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Alice A Gibson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Yang Li
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kristen W Hong
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Duncan DiGiacomo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Sherry H Xia
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Paola Alberti
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,NeuroMI, Milan Center for Neuroscience, Milan, Italy
| | - Alessia Chiorazzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,NeuroMI, Milan Center for Neuroscience, Milan, Italy
| | - Stephen N Housley
- School of Biological Sciences and Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Timothy C Cope
- School of Biological Sciences and Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Jason A Sprowl
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Jing Wang
- Department of Cancer Biology and Genetics, College of Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Charles L Loprinzi
- Department of Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota, USA
| | - Anne Noonan
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Maryam B Lustberg
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Guido Cavaletti
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,NeuroMI, Milan Center for Neuroscience, Milan, Italy
| | - Navjot Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| |
Collapse
|