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Haffez H, Sanad HH, Ebrahim H, Hassan ZA. Synergistic effects of abietic acid combined with doxorubicin on apoptosis induction in a human colorectal cancer cell line. Sci Rep 2025; 15:16102. [PMID: 40341222 PMCID: PMC12062260 DOI: 10.1038/s41598-025-99616-2] [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: 01/07/2025] [Accepted: 04/21/2025] [Indexed: 05/10/2025] Open
Abstract
Cancer is a significant global disease with high mortality and limited therapeutic options. Chemotherapy is a cancer treatment option; however, there are still issues, including severe side effects, inadequate response, and drug resistance. Abietic acid is a natural diterpene with diverse pharmacological properties and can be used for cancer treatment. Therefore, this study aimed to assess the anticancer efficacy of abietic acid in combination with doxorubicin, a highly clinically used chemotherapeutic agent. Biochemical investigations include initial viability assays, combination therapy using isobologram analysis, apoptosis and cell cycle assays, gene expression assay, ELISA analysis of protein expression, DNA fragmentation, and wound healing assays. The data showed that doxorubicin-abietic acid (DOX-AB) is an effective and safe anticancer combination for Caco-2 cells. DOX-AB had a high safety index with minimal cytotoxicity at the combination dose on normal WI-38 fibroblasts cells. DOX-AB significantly decreased the proliferation and viability of Caco-2 cells, with an increase in the apoptosis rate in the late stage and necrosis with cell cycle arrest at the G2/M phase. Significant changes in the expression of modulators related to apoptosis, inflammation, and epigenetics were observed in gene and protein levels. DOX-AB combination had more efficient anticancer activity than doxorubicin alone. This study suggested that the use of abietic acid in combination with doxorubicin is a promising treatment for colorectal cancer because it enhances doxorubicin activity at relatively low doses with minimal cytotoxicity and overcomes multidrug resistance in tumors; these findings merit further investigation.
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Affiliation(s)
- Hesham Haffez
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo, 11795, Egypt.
- Center of Scientific Excellence "Helwan Structural Biology Research, (HSBR)", Helwan University, Cairo, 11795, Egypt.
| | - Hend H Sanad
- Health Affairs Directorate, Mansoura Health Administration, Mansura city, , El Dakahlia, Egypt
| | - Hassan Ebrahim
- Pharmacognosy Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt
| | - Zeineb A Hassan
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo, 11795, Egypt
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Elfiky A, El-Guendy N, Badr AM, Mohammed MA, Wahab AHAA. The role of FOXA1 and miR-212-3p in molecular modulation of doxorubicin resistance in liver cancer. Med Oncol 2025; 42:160. [PMID: 40216647 PMCID: PMC11991990 DOI: 10.1007/s12032-025-02686-5] [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: 12/24/2024] [Accepted: 03/11/2025] [Indexed: 04/14/2025]
Abstract
TACE (Transarterial Chemoembolization) is an essential current treatment for liver cancer. Resistance to doxorubicin, the chemotherapeutic component of TACE, poses a serious problem in this treatment, necessitating a deeper understanding of the underlying resistance mechanisms. Upregulation of the Forkhead box A1 transcription regulator in our model of doxorubicin-resistant liver cancer cell line suggested a role in resistance. To better understand the role of FOXA1 in resistance to doxorubicin, we inhibited its expression using siRNA or its miRNA-212-3p inhibitor then studied the effect on the cancer cell lines survival using SRB assay. The expression of several downstream epithelial-mesenchymal transition genes, namely SLUG, TWIST, CDH1 (E-Cadherin), was determined using quantitative real-time PCR. Our results showed a significant upregulation of FOXA1 and downregulation of miRNA-212-3p in doxorubicin-resistant cells. Manipulation of FOXA1 and miRNA-212-3p expressions restored sensitive cell characteristics. In addition, inhibition of FOXA1 increased apoptosis induction in resistant cells. Changes detected in the tested EMT genes point to progression toward more aggressive behavior in the doxorubicin-resistant liver cancer cell line that was reversed with inhibition of FOXA1. Our results suggest a possible role of FOXA1 and miRNA-212-3p in the development of resistance to chemotherapeutic drugs in liver cancer and the possibility of their use as prognostic and/or therapeutic targets.
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Affiliation(s)
- Ammar Elfiky
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt
| | - Nadia El-Guendy
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt
| | - Abeer Mahmoud Badr
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Mohammed Aly Mohammed
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt
| | - Abdel Hady A Abdel Wahab
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt.
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Bełdzińska P, Zakrzewski M, Mruk I, Bogusławski M, Derewońko N, Bury K, Wyrzykowski D, Gołuński G, Rychłowski M, Piosik J. Size dependent impact of platinum nanoparticles on doxorubicin activity. Eur J Pharm Sci 2025; 209:107094. [PMID: 40187539 DOI: 10.1016/j.ejps.2025.107094] [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: 02/03/2025] [Revised: 03/26/2025] [Accepted: 04/03/2025] [Indexed: 04/07/2025]
Abstract
Cancer is a leading cause of death worldwide, with nearly 10 million fatalities yearly. Consequently, despite the search for new therapeutic approaches, the use of classical chemotherapy, remains one of the main treatment regimens. Therefore, we evaluate the use of platinum nanoparticles (PtNPs) of different sizes as potential modulators of doxorubicin (DOX) activity. In the presented research, we utilized a wide range of methods, including Spectroscopic measurements, Isothermal Titration Calorimetry, Dynamic Light Scattering, and Atomic Force Microscopy, as well as biological assays such as the Ames mutagenicity test on Salmonella enterica serovar Typhimurium TA98 and the alamarBlue cytotoxicity assay with Fluorescent Confocal Microscopy on non-cancerous HaCaT and cancerous MelJuSo cell lines, to investigate the interactions between PtNPs and DOX and the effect of diverse-sized nanoparticles on DOX activity. The obtained results indicate the presence of direct interactions, particularly highlighting differences related to particles size. We confirmed that DOX affects the aggregation of nanoparticles, while the nanoparticles induce DOX fluorescence quenching. In terms of biological aspects, PtNPs reduced the mutagenicity of DOX, and increased the survival of non-cancerous HaCaT cells. Furthermore, 70 nm PtNPs significantly increased DOX effects on cancerous MelJuSo cells by negatively affecting their morphology and culture density. To conclude, our research provided valuable insights into the interactions between PtNPs and DOX with particular emphasis on the nanoparticles' size influence highlighting nanoparticles' impact on DOX cytotoxicity providing a base for further research on the potential future modification in treatment approaches.
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Affiliation(s)
| | | | - Inez Mruk
- Laboratory of Biophysics, University of Gdańsk, Gdańsk, Poland.
| | | | - Natalia Derewońko
- Laboratory of Recombinant Vaccines, University of Gdansk, Gdansk, Poland.
| | - Katarzyna Bury
- Laboratory of Molecular Biology, University of Gdańsk, Gdańsk, Poland.
| | - Dariusz Wyrzykowski
- Department of General and Inorganic Chemistry, University of Gdansk, Gdansk, Poland.
| | | | - Michał Rychłowski
- Laboratory of Virus Molecular Biology, University of Gdansk, Gdansk, Poland.
| | - Jacek Piosik
- Laboratory of Biophysics, University of Gdańsk, Gdańsk, Poland.
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Han X, Zhang X, Kang L, Feng S, Li Y, Zhao G. Peptide-modified nanoparticles for doxorubicin delivery: Strategies to overcome chemoresistance and perspectives on carbohydrate polymers. Int J Biol Macromol 2025; 299:140143. [PMID: 39855525 DOI: 10.1016/j.ijbiomac.2025.140143] [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: 12/16/2024] [Revised: 01/07/2025] [Accepted: 01/20/2025] [Indexed: 01/27/2025]
Abstract
Chemotherapy serves as the primary treatment for cancers, facing challenges due to the emergence of drug resistance. Combination therapy has been developed to combat cancer drug resistance, yet it still suffers from lack of specific targeting of cancer cells and poor accumulation at the tumor site. Consequently, targeted administration of chemotherapy medications has been employed in cancer treatment. Doxorubicin (DOX) is one of the most frequently used chemotherapeutics, functioning by inhibiting topoisomerase activity. Enhancing the anti-cancer effects of DOX and overcoming drug resistance can be accomplished via delivery by nanoparticles. This review will focus on the development of peptide-DOX conjugates, the functionalization of nanoparticles with peptides, the co-delivery of DOX and peptides, as well as the theranostic use of peptide-modified nanoparticles in cancer treatment. The peptide-DOX conjugates have been designed to enhance the targeted delivery to cancer cells by interacting with receptors that are overexpressed on tumor surfaces. Moreover, nanoparticles can be modified with peptides to improve their uptake in tumor cells via endocytosis. Nanoparticles have the ability to co-deliver DOX along with therapeutic peptides for enhanced cancer treatment. Finally, nanoparticles modified with peptides can offer theranostic capabilities by facilitating both imaging and the delivery of DOX (chemotherapy).
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Affiliation(s)
- Xu Han
- Department of Traditional Chinese medicine, The First Hospital of China Medical University, Shenyang, China
| | - Xue Zhang
- Department of Gynecology, The First Hospital of China Medical University, Shenyang, China
| | - Longdan Kang
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, China
| | - Shuai Feng
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, China.
| | - Yinyan Li
- Department of Ultrasonic Diagnosis, The First Hospital of China Medical University, Shenyang, China.
| | - Ge Zhao
- Department of Obstetrics, The First Hospital of China Medical University, Shenyang, China.
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Tressler CM, Sonkar K, Cheng M, Ayyappan V, Cai R, Glunde K. Molecular effects of clinically relevant chemotherapeutic agents on choline phospholipid metabolism in triple negative breast cancer cells. Transl Oncol 2025; 53:102311. [PMID: 39922048 PMCID: PMC11849126 DOI: 10.1016/j.tranon.2025.102311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 12/21/2024] [Accepted: 01/30/2025] [Indexed: 02/10/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is the most lethal breast cancer subtype, leading to poor patient outcomes despite aggressive treatment with surgery, radiation, and chemotherapy. There are currently no clinical tests available which measure early on whether TNBC patients respond to the selected chemotherapy treatment regimen. The magnetic resonance spectroscopy (MRS)-detected total choline (tCho) signal was shown to be a promising biomarker for assessing the response to chemotherapy treatment early on, as breast tumor tCho decreases after the first treatment cycle in patients who respond to chemotherapy cocktails. We sought to further investigate these clinical observations at the molecular level by combining metabolic and transcriptomic studies in two human TNBC cell lines treated with six different chemotherapeutic agents. Overall, our findings show that the glycerophosphocholine-to-phosphocholine ratio (GPC/PC) was a more sensitive and more broadly applicable measure of TNBC response to various chemotherapeutic agents than tCho. Specific chemotherapeutic drugs, including 5-fluorouracil and melphalan, resulted in the most significant effects on choline phospholipid metabolism, while other drugs did not significantly alter choline phospholipid metabolism. Overall, several of the six tested chemotherapeutic drugs mainly affected the expression levels of phosphatidylcholine (PtdC)-specific phospholipases and lysophospholipases, leading to the observed GPC/PC and tCho changes following treatment with the chemotherapeutic agents that altered choline phospholipid metabolism. The presented metabolic and transcriptomic findings support that the GPC/PC ratio and PtdC-phospholipases and -lysophospholipases could be further developed for assessing the response to chemotherapy treatment in TNBC patients. Statement of Significance: We show that the glycerophosphocholine-to-phosphocholine ratio and phosphatidylcholine-specific-phospholipases and -lysophospholipases are reliable markers for assessing the response to several chemotherapeutic agents, which could help with selecting correct treatments for TNBC patients.
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Affiliation(s)
- Caitlin M Tressler
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kanchan Sonkar
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Menglin Cheng
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Vinay Ayyappan
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruoqing Cai
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kristine Glunde
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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Choi YH, Kim HY, Park JO, Choi E. Enhanced Anti-Tumor Effects of Natural Killer Cell-Derived Exosomes Through Doxorubicin Delivery to Hepatocellular Carcinoma Cells: Cytotoxicity and Apoptosis Study. Int J Mol Sci 2025; 26:2234. [PMID: 40076856 PMCID: PMC11900065 DOI: 10.3390/ijms26052234] [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: 01/17/2025] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Exosomes are nanosized extracellular vesicles secreted by various cells, including natural killer (NK) cells, and are known for their low toxicity, high permeability, biocompatibility, and strong targeting ability. NK cell-derived exosomes (NK-exos) contain cytotoxic proteins that enhance tumor-targeting efficiency, making them suitable for treating solid tumors such as hepatocellular carcinoma (HCC). Despite their potential in drug delivery, the mechanisms of drug-loaded NK-exos, particularly those loaded with doxorubicin (NK-exos-Dox), remain unclear in HCC. This study explored the anti-tumor effects of NK-exos-Dox against Hep3B cells in vitro. NK-exos-Dox expressed exosome markers (CD9 and CD63) and cytotoxic proteins (granzyme B and perforin) and measured 170-220 nm in size. Compared to NK-exos, NK-exos-Dox enhanced cytotoxicity and apoptosis in Hep3B cells by upregulating pro-apoptotic proteins (Bax, cytochrome c, cleaved caspase 3, and cleaved PARP) and inhibiting the anti-apoptotic protein (Bcl-2). These findings suggest that NK-exos-Dox significantly boost anti-tumor effects by activating specific cytotoxic molecules, offering promising therapeutic opportunities for solid tumor treatment, including HCC.
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Affiliation(s)
- You Hee Choi
- Korea Institute of Medical Microrobotics, 43-26 Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea; (H.Y.K.); (J.-O.P.)
| | - Ho Yong Kim
- Korea Institute of Medical Microrobotics, 43-26 Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea; (H.Y.K.); (J.-O.P.)
| | - Jong-Oh Park
- Korea Institute of Medical Microrobotics, 43-26 Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea; (H.Y.K.); (J.-O.P.)
| | - Eunpyo Choi
- Department of Mechanical Engineering, Sogang University, 35, Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
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Lim JX, Yong YK, Dewi FRP, Chan SY, Lim V. Nanoscale strategies: doxorubicin resistance challenges and enhancing cancer therapy with advanced nanotechnological approaches. Drug Deliv Transl Res 2025:10.1007/s13346-025-01790-3. [PMID: 39955406 DOI: 10.1007/s13346-025-01790-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2025] [Indexed: 02/17/2025]
Abstract
Doxorubicin (DOX), an anthracycline, is widely used in cancer treatment by interfering RNA and DNA synthesis. Its broad antitumour spectrum makes it an effective therapy for a wide array of cancers. However, the prevailing drug-resistant cancer has proven to be a significant drawback to the success of the conventional chemotherapy regime and DOX has been identified as a major hurdle. Furthermore, the clinical application of DOX has been limited by rapid breakdown, increased toxicity, and decreased half-time life, highlighting an urgent need for more innovative delivery methods. Although advancements have been made, achieving a complete cure for cancer remains elusive. The development of nanoparticles offers a promising avenue for the precise delivery of DOX into the tumour microenvironment, aiming to increase the drug concentration at the target site while reducing side effects. Despite the good aspects of this technology, the classical nanoparticles struggle with issues such as premature drug leakage, low bioavailability, and insufficient penetration into tumours due to an inadequate enhanced permeability and retention (EPR) effect. Recent advancements have focused on creating stimuli-responsive nanoparticles and employing various chemosensitisers, including natural compounds and nucleic acids, fortifying the efficacy of DOX against resistant cancers. The efforts to refine nanoparticle targeting precision to improve DOX delivery are reviewed. This includes using receptor-mediated endocytosis systems to maximise the internalisation of drugs. The potential benefits and drawbacks of these novel techniques constitute significant areas of ongoing study, pointing to a promising path forward in addressing the challenges posed by drug-resistant cancers.
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Affiliation(s)
- Jian Xin Lim
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200 Kepala Batas, Penang, Malaysia
| | - Yoke Keong Yong
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Firli Rahmah Primula Dewi
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Siok Yee Chan
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Pulau Pinang, Malaysia
| | - Vuanghao Lim
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200 Kepala Batas, Penang, Malaysia.
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Mekonnen N, Yang H, Rajasekaran N, Song K, Choi YL, Shin YK. Indirect targeting of MYC and direct targeting in combination with chemotherapies are more effective than direct mono-targeting in triple negative breast cancer. Transl Oncol 2025; 51:102204. [PMID: 39631207 DOI: 10.1016/j.tranon.2024.102204] [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: 05/15/2024] [Revised: 10/20/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
MYC amplification is disproportionally elevated in triple-negative breast cancer (TNBC) compared to other subtypes of breast cancer. Indeed, MYC has long been considered an undruggable oncogene using conventional drug design strategies or small molecules. We hypothesized that targeting MYC using asymmetric siRNA (asiRNA) alone or in combination with chemotherapeutic agents or indirectly via BRD4 and RRM2, may curb its oncogenic behavior. We developed paclitaxel-, doxorubicin-, and cisplatin-resistant MDA-MB-231 cells to study MYC's role in upregulating DNA repair genes during drug resistance development. Our results showed that the knockdown of either MYC or RRM2 downregulated both RAD51 and PARP1 but increased γH2AX. The cytotoxic effect of RRM2 knockdown was significantly (p < 0.05) higher than that of direct MYC knockdown. The knockdown of BRD4 was more effective than the direct knockdown of MYC in downregulating MYC protein. The combined use of asiRNA-VP (Vinylphosphonate) with dacomitinib or talazoparib was synthetic lethal in TNBC cell lines. Compared to chemotherapy-sensitive cells, resistant cells showed overexpression of MYC, RRM2, RAD51, and PARP1 proteins upon chemotherapy treatment, but downregulated in cells treated with asiRNA-VP combination. We confirmed that MYC knockdown upregulated cFLIP, BCL2, STAT1, pSTAT1, STAT2, and cleaved saspase-3 in both TNBC and non-small cell lung cancer (NSCLC) cell lines. Finally, we recommend a combination treatment approach that synergizes with MYC inhibition rather than monotherapy or indirect targeting via upstream regulators such as the BRD4 and RRM2 genes or selective modulation at the protein level to suppress anti-apoptotic genes (cFLIP and BCL2) at the same time.
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Affiliation(s)
- Negesse Mekonnen
- Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, College of Pharmacy, Seoul, South Korea; Department of Veterinary Science, School of Animal Science and Veterinary Medicine, Bahir Dar University, Bahir Dar, Ethiopia.
| | - Hobin Yang
- College of Pharmacy, Kyungsung University, Busan, South Korea.
| | | | - Kyoung Song
- College of Pharmacy, Duksung Women's University, Seoul, South Korea.
| | - Yoon-La Choi
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea; Laboratory of Molecular Pathology and Theranostics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Young Kee Shin
- Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, College of Pharmacy, Seoul, South Korea; R&D Center, ABION Inc., Seoul 08394, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Graduate School of Convergence Science and Technology, Seoul, South Korea; Bio-MAX/N-Bio, Seoul National University, Seoul, South Korea.
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Munir I, Nazir F, Yesiloz G. Unlocking Nature's Potential: Ferritin as a Universal Nanocarrier for Amplified Cancer Therapy Testing via 3D Microtissues. ACS APPLIED MATERIALS & INTERFACES 2024; 16:70187-70204. [PMID: 39660468 DOI: 10.1021/acsami.4c12524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2024]
Abstract
In the existing development of extensive drug screening models, 3D cell cultures outshine conventional 2D monolayer cells by closely imitating the in vivo tumor microenvironment. This makes 3D culture a more physiologically relevant and convenient system in the regime of preclinical drug testing. In the nanomedicinal world, nanoconjugates as nanocarriers are largely hunted due to their capability of precisely binding to target cells and distributing essential dosages of therapeutic drugs with enhanced safety profiles. Thus, for boosted drug availability, the evolution from conventional drug treatment to combination therapies and last switching to drug carriers has gained significant progression in cancer cure. In contrast to conventional engineered nanoparticles, herein, we successfully designed biomolecule (ferritin)-based drug nanoconjugates effective both as a single drug (valproic acid-VPA) and twin-drug (valproic acid/doxorubicin-Dox) carriers, which dramatically enhance the proficiency of the tumor therapeutic modality. To question the reported adjuvant drug property of VPA, we progressed utilizing at first VPA alone as an effective yet exclusive tumor therapy when delivered via some carrier molecule, in particular protein. Subsequently, we paralleled this comprehensive investigation output to compare and test the coloading strategy of drugs and observe the synergistic and/or additive behavior of VPA in conjugation with other anticancer agents (Dox) while given via a carrier molecule. To approach this, VPA and/or Dox molecules were encapsulated into the ferritin (F) cavity using a thermosensitive synthesis method by maintaining the temperature at 60 °C. The successful encapsulation of drugs in the protein nanocage was confirmed through various characterization techniques. The F-VPA/F-VPA-Dox nanoconjugates exhibited similar morphology and structural characteristics to the hollow ferritin cage and showed significant cytotoxicity than the naked drugs when tested on physiologically relevant 3D spheroid models. Precisely, our first designed carrier nanoconjugate, i.e., F-VPA, offered more than a 3-fold increased intratumoral drug concentration than free VPA and significantly suppressed tumor growth after a single-dose treatment. However, our second modeled carrier nanoconjugate, viz. F-VPA-Dox, revealed an extended median survival period and lesser toxicity when administered at a much more effective dose (∼3-5 μM), in 3D tumor spheroid models of various cancer cell lines. All in all, importantly, ferritin nanoconjugates exhibited an enhanced tumor inhibition rate with a single-dose treatment, which further confirms the benefits of the active targeting property of these nanocarriers. Moreover, these nanocarriers also offer to deliver a significant dose of the therapeutic drug into tumor cells, alongside tremendous biocompatibility and safety profiles in numerous tumor 3D spheroid models.
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Affiliation(s)
- Iqra Munir
- National Nanotechnology Research Center (UNAM) Bilkent University, Cankaya, Ankara, 06800, Türkiye
| | - Faiqa Nazir
- National Nanotechnology Research Center (UNAM) Bilkent University, Cankaya, Ankara, 06800, Türkiye
- Institute of Material Science and Nanotechnology, Bilkent University, Cankaya, Ankara, 06800, Türkiye
| | - Gurkan Yesiloz
- National Nanotechnology Research Center (UNAM) Bilkent University, Cankaya, Ankara, 06800, Türkiye
- Institute of Material Science and Nanotechnology, Bilkent University, Cankaya, Ankara, 06800, Türkiye
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10
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Basheer I, Wang H, Li G, Jehan S, Raza A, Du C, Ullah N, Li D, Sui G. β-caryophyllene sensitizes hepatocellular carcinoma cells to chemotherapeutics and inhibits cell malignancy through targeting MAPK signaling pathway. Front Pharmacol 2024; 15:1492670. [PMID: 39734415 PMCID: PMC11671526 DOI: 10.3389/fphar.2024.1492670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 11/27/2024] [Indexed: 12/31/2024] Open
Abstract
Background β-caryophyllene (BCP) is a naturally occurring bicyclic sesquiterpene extracted from various plants, and widely used as a medicinal agent for various diseases. During hepatocellular carcinoma (HCC) development, cancer cells generally exhibit increased cell proliferation due to mutations or aberrant expression of key regulatory genes. The current study determines the cytotoxic effects of BCP alone or in combination with doxorubicin (DOX) and cisplatin (DDP) on HCC cells, and elucidates the underlying mechanism of BCP to exert its anticancer activities. Materials and methods HepG2, SMMC-7721 HCC cells, and HL-7702 normal liver cells were treated with BCP, DOX, and DDP individually or combinatorially. Cell proliferation assay, flow cytometric assay, and Western blot were employed to evaluate the cytotoxic effects of these treatments. Transwell assays were used to examine BCP's effects on HCC cell migration and invasion. RNA-seq analysis was used to determine BCP's primary target genes in HepG2 cells. Integrative analysis of differentially expressed genes (DEGs) of RNA-seq data with an HCC TCGA dataset identified BCP-targeted genes that were verified by RT-qPCR analysis. Ectopic gene expression, cell viability, and colony formation assay were performed to validate the primary targets of BCP. Results BCP selectively inhibited HCC cell proliferation while exhibited relatively low toxicity in normal liver cells; however, DOX and DDP showed higher toxicity in normal cells than that in HCC cells. In combinatorial treatments, BCP synergistically enhanced cytotoxicity of DOX and DDP in HCC cells but this effect was markedly reduced in HL-7702 cells. BCP treatment reduced migration and invasion of HCC cells. Furthermore, RNA-seq analyses of BCP-treated HepG2 cells identified 433 protein-coding DEGs. Integrative analyses revealed five BCP-targeted DEGs regulating the MAPK signaling pathway. Among these five genes, three displayed a significantly positive correlation of their expression with the overall survival of HCC patients. As a primary target, PGF was significantly downregulated by BCP treatment, and its exogenous expression desensitized HCC cells to BCP-mediated inhibition. Discussion BCP inhibits malignant properties of HCC and synergistically sensitizes the anticancer activity of DOX and DDP. In HCC cells, BCP primarily targets the PGF gene and MAPK signaling pathway.
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Affiliation(s)
- Irum Basheer
- Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, China
| | - Hai Wang
- Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, China
| | - Guangyue Li
- Intelligent Biomedical Labs, Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Shah Jehan
- Department of Vascular Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ali Raza
- Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, China
| | - Chentao Du
- Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, China
| | - Najeeb Ullah
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Dangdang Li
- Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, China
| | - Guangchao Sui
- Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, China
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11
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Lu XY, Jin H. MiRNAs function in the development of resistance against doxorubicin in cancer cells: targeting ABC transporters. Front Pharmacol 2024; 15:1486783. [PMID: 39679367 PMCID: PMC11638538 DOI: 10.3389/fphar.2024.1486783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 10/23/2024] [Indexed: 12/17/2024] Open
Abstract
Resistance to chemotherapeutic agents poses a significant challenge in cancer treatment, particularly with doxorubicin, a widely used drug for various cancers, including breast cancer, leukaemia, osteosarcoma, and gastrointestinal cancers. This review aims to elucidate the critical role of microRNAs (miRNAs) in the development of doxorubicin resistance, focusing on their interactions with ATP-binding cassette (ABC) transporters. Despite extensive research, the molecular mechanisms governing doxorubicin resistance still need to be completed, particularly regarding the regulatory influence of miRNAs on ABC transporter expression. By analyzing current literature, this review identifies a notable gap: the lack of comprehensive insight into how specific miRNAs modulate the expression and activity of ABC transporters in cancer cells, contributing to doxorubicin resistance. We systematically examine recent findings on the interplay between miRNAs and ABC transporters, providing a detailed assessment of potential therapeutic strategies that leverage miRNA modulation to overcome drug resistance. Ultimately, this review underscores the significance of integrating miRNA research into existing therapeutic frameworks to enhance the efficacy of doxorubicin in cancer treatment.
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Affiliation(s)
- Xin-Yan Lu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hongxu Jin
- Emergency Medicine Department of General Hospital of Northern Theater Command, Shenyang, Liaoning, China
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12
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Machuca A, Peñalver GA, Garcia RAF, Martinez-Lopez A, Castillo-Lluva S, Garcia-Calvo E, Luque-Garcia JL. Advancing rhodium nanoparticle-based photodynamic cancer therapy: quantitative proteomics and in vivo assessment reveal mechanisms targeting tumor metabolism, progression and drug resistance. J Mater Chem B 2024; 12:12073-12086. [PMID: 39453320 DOI: 10.1039/d4tb01631a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
Rhodium nanoparticles have been recently discovered as good photosensitizers with great potential in cancer photodynamic therapy by effectively inducing cytotoxicity in cancer cells under near-infrared laser. This study evaluates the molecular mechanisms underlying such antitumoral effect through quantitative proteomics. The results revealed that rhodium nanoparticle-based photodynamic therapy disrupts tumor metabolism by downregulating key proteins involved in ATP synthesis and mitochondrial function, leading to compromised energy production. The treatment also induces oxidative stress and apoptosis while targeting the invasion capacity of cancer cells. Additionally, key proteins involved in drug resistance are also affected, demonstrating the efficacy of the treatment in a multi-drug resistant cell line. In vivo evaluation using a chicken embryo model also confirmed the effectiveness of the proposed therapy in reducing tumor growth without affecting embryo viability.
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Affiliation(s)
- Andres Machuca
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Gabriel A Peñalver
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | | | - Angelica Martinez-Lopez
- Department Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Sonia Castillo-Lluva
- Department Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Estefania Garcia-Calvo
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Jose L Luque-Garcia
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
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13
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Minisini M, Mascaro M, Brancolini C. HDAC-driven mechanisms in anticancer resistance: epigenetics and beyond. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:46. [PMID: 39624079 PMCID: PMC11609180 DOI: 10.20517/cdr.2024.103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/24/2024] [Accepted: 11/07/2024] [Indexed: 01/03/2025]
Abstract
The emergence of drug resistance leading to cancer recurrence is one of the challenges in the treatment of cancer patients. Several mechanisms can lead to drug resistance, including epigenetic changes. Histone deacetylases (HDACs) play a key role in chromatin regulation through epigenetic mechanisms and are also involved in drug resistance. The control of histone acetylation and the accessibility of regulatory DNA sequences such as promoters, enhancers, and super-enhancers are known mechanisms by which HDACs influence gene expression. Other targets of HDACs that are not histones can also contribute to resistance. This review describes the contribution of HDACs to the mechanisms that, in some cases, may determine resistance to chemotherapy or other cancer treatments.
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Affiliation(s)
| | | | - Claudio Brancolini
- Laboratory of Epigenomics, Department of Medicine, Università degli Studi di Udine, Udine 33100, Italy
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14
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Garcia CJC, Grisetti L, Tiribelli C, Pascut D. The ncRNA-AURKA Interaction in Hepatocellular Carcinoma: Insights into Oncogenic Pathways, Therapeutic Opportunities, and Future Challenges. Life (Basel) 2024; 14:1430. [PMID: 39598228 PMCID: PMC11595987 DOI: 10.3390/life14111430] [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: 08/30/2024] [Revised: 10/15/2024] [Accepted: 11/03/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major public health concern and ranks among the leading cancer-related mortalities globally. Due to the frequent late-stage diagnosis of HCC, therapeutic options remain limited. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) in the regulation of Aurora kinase A (AURKA), one of the key hub genes involved in several key cancer pathways. Indeed, the dysregulated interaction between ncRNAs and AURKA contributes to tumor development, progression, and therapeutic resistance. This review delves into the interplay between ncRNAs and AURKA and their role in hepatocarcinogenesis. Recent findings underscore the involvement of the ncRNAs and AURKA axis in tumor development and progression. Furthermore, this review also discusses the clinical significance of targeting ncRNA-AURKA axes, offering new perspectives that could lead to innovative therapeutic strategies aimed at improving outcomes for HCC patients.
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Affiliation(s)
- Clarissa Joy C. Garcia
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
- Department of Life Sciences, Università degli Studi di Trieste, 34127 Trieste, Italy
| | - Luca Grisetti
- National Institute of Gastroenterology—IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy
| | - Claudio Tiribelli
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
| | - Devis Pascut
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
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15
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Song L, Qiu Q, Ju F, Zheng C. Mechanisms of doxorubicin-induced cardiac inflammation and fibrosis; therapeutic targets and approaches. Arch Biochem Biophys 2024; 761:110140. [PMID: 39243924 DOI: 10.1016/j.abb.2024.110140] [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: 07/14/2024] [Revised: 08/28/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024]
Abstract
Doxorubicin plays a pivotal role in the treatment of various malignancies. Despite its efficacy, the cardiotoxicity associated with doxorubicin limits its clinical utility. The cardiotoxic nature of doxorubicin is attributed to several mechanisms, including its interference with mitochondrial function, the generation of reactive oxygen species (ROS), and the subsequent damage to cardiomyocyte DNA, proteins, and lipids. Furthermore, doxorubicin disrupts the homeostasis of cardiac-specific transcription factors and signaling pathways, exacerbating cardiac dysfunction. Oxidative stress, cell death, and other severe changes, such as mitochondrial dysfunction, activation of pro-oxidant enzymes, the renin-angiotensin system (RAS), endoplasmic reticulum (ER) stress, and infiltration of immune cells in the heart after treatment with doxorubicin, may cause inflammatory and fibrotic responses. Fibrosis and inflammation can lead to a range of disorders in the heart, resulting in potential cardiac dysfunction and disease. Various adjuvants have shown potential in preclinical studies to mitigate these challenges associated with cardiac inflammation and fibrosis. Antioxidants, plant-based products, specific inhibitors, and cardioprotective drugs may be recommended to alleviate cardiotoxicity. This review explores the complex mechanisms of doxorubicin-induced heart inflammation and fibrosis, identifies possible cellular and molecular targets, and investigates potential substances that could help reduce these harmful effects.
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Affiliation(s)
- Linghua Song
- Department of Pharmacy, Yantai Mountain Hospital, Yantai City, Shandong Province, 264001, China
| | - Qingzhuo Qiu
- Medical Imaging Department of Qingdao Women and Children's Hospital, 266000, China
| | - Fei Ju
- Department of Critical Care, Medicine East Hospital of Qingdao Municipal Hospital, 266000, China
| | - Chunyan Zheng
- Cadre Health Office of Zibo Central Hospital in Shandong Province, 255000, China.
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16
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Arora R, Mukherjee A, Arthur G, Nachtigal MW, Schweizer F. Modulating polybasic character of galactose-based glycosylated antitumor ether lipids for enhanced cytotoxic response. RSC Med Chem 2024; 16:d4md00662c. [PMID: 39464652 PMCID: PMC11499978 DOI: 10.1039/d4md00662c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 10/11/2024] [Indexed: 10/29/2024] Open
Abstract
We describe the structure-activity relationship studies of galactose-based glycosylated antitumor ether lipids (GAELs) by installing amine groups at different positions of galactose and the glycerol backbone. Different dibasic and tribasic analogues of galacto-GAELs were synthesized and tested against a panel of human epithelial cancer cell lines. A β-anomeric triamino galactose scaffold, was the most active compound of the series and displayed CC50 in the range of 2.6 ± 0.2 μM to 6.5 ± 0.1 μM against various epithelial cancer cell lines. This compound exhibited superior activity to kill cancer cells than cisplatin. The hit GAEL compound did not induce caspase activation and therefore, the cell-killing effect does not occur due to caspase-mediated apoptosis. This observation is in line with the previously reported GAEL prototypes.
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Affiliation(s)
- Rajat Arora
- Department of Chemistry, Faculty of Science, University of Manitoba Winnipeg Manitoba R3T 2N2 Canada
| | - Ayan Mukherjee
- Department of Chemistry, Faculty of Science, University of Manitoba Winnipeg Manitoba R3T 2N2 Canada
| | - Gilbert Arthur
- Department of Biochemistry and Medical Genetics, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
| | - Mark W Nachtigal
- Department of Biochemistry and Medical Genetics, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
- Paul Albrechtsen Research Institute, CancerCare Manitoba Winnipeg Manitoba R3E 0V9 Canada
| | - Frank Schweizer
- Department of Chemistry, Faculty of Science, University of Manitoba Winnipeg Manitoba R3T 2N2 Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
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17
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Vaghari-Tabari M, Qujeq D, Hashemzadeh MS. Long noncoding RNAs as potential targets for overcoming chemoresistance in upper gastrointestinal cancers. Biomed Pharmacother 2024; 179:117368. [PMID: 39214010 DOI: 10.1016/j.biopha.2024.117368] [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: 05/27/2024] [Revised: 08/16/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
In the last decade, researchers have paid much attention to the role of noncoding RNA molecules in human diseases. Among the most important of these molecules are LncRNAs, which are RNA molecules with a length of more than 200 nucleotides. LncRNAs can regulate gene expression through various mechanisms, such as binding to DNA sequences and interacting with miRNAs. Studies have shown that LncRNAs may be valuable therapeutic targets in treating various cancers, including upper-gastrointestinal cancers. Upper gastrointestinal cancers, mainly referring to esophageal and gastric cancers, are among the deadliest gastrointestinal cancers. Despite notable advances, traditional chemotherapy remains a common strategy for treating these cancers. However, chemoresistance poses a significant obstacle to the effective treatment of upper gastrointestinal cancers, resulting in a low survival rate. Chemoresistance arises from various events, such as the enhancement of efflux and detoxification of chemotherapy agents, reduction of drug uptake, alteration of drug targeting, reduction of prodrug activation, strengthening of EMT and stemness, and the attenuation of apoptosis in cancerous cells. Tumor microenvironment also plays an important role in chemoresistance. Interestingly, a series of studies have revealed that LncRNAs can influence important mechanisms associated with some of the aforementioned events and may serve as promising targets for mitigating chemoresistance in upper gastrointestinal cancers. In this review paper, following a concise overview of chemoresistance mechanisms in upper gastrointestinal cancers, we will review the most intriguing findings of these investigations in detail.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
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18
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Sharma AK, Sharma R, Chauhan N, Das A, Satpati D. Peptide-drug conjugate designated for targeted delivery to HER2-expressing cancer cells. J Pept Sci 2024; 30:e3602. [PMID: 38600778 DOI: 10.1002/psc.3602] [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: 01/16/2024] [Revised: 02/15/2024] [Accepted: 03/19/2024] [Indexed: 04/12/2024]
Abstract
Targeted therapy of the highest globally incident breast cancer shall resolve the issue of off-target toxicity concurring with augmented killing of specific diseased cells. Thus, the goal of this study was to prepare a peptide-drug conjugate targeting elevated expression of HER2 receptors in breast cancer. Towards this, the rL-A9 peptide was conjugated with the chemotherapeutic drug doxorubicin (DOX) through a N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker. The synthesized peptide-drug conjugate, rL-A9-DOX, was characterized by mass spectrometry. Molecular docking studies, based on binding energy data, suggested a stronger interaction of rL-A9-DOX with the HER2 receptor in comparison to the unconjugated peptide, rL-A9. The cytotoxic effect of the rL-A9-DOX conjugate was observed to be higher in HER2-positive SKOV3 cells compared to HER2-negative MDA-MB-231 cells, indicating selective cell killing. Cellular internalization of the rL-A9-DOX conjugate was evident from the flow cytometry analysis, where a noticeable shift in mean fluorescent intensity (MFI) was observed for the conjugate compared to the control group. This data was further validated by confocal microscopy, where the fluorescent signal ascertained nuclear accumulation of rL-A9-DOX. The present studies highlight the promising potential of rL-A9-DOX for targeted delivery of the drug into a defined group of cancer cells.
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Affiliation(s)
- Amit Kumar Sharma
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Rohit Sharma
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Nitish Chauhan
- Homi Bhabha National Institute, Mumbai, India
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Amit Das
- Homi Bhabha National Institute, Mumbai, India
- Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Drishty Satpati
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
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19
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Qiao X, van der Zanden SY, Li X, Tan M, Zhang Y, Song JY, van Gelder MA, Hamoen FL, Janssen L, Zuur CL, Pang B, van Tellingen O, Li J, Neefjes J. Diversifying the anthracycline class of anti-cancer drugs identifies aclarubicin for superior survival of acute myeloid leukemia patients. Mol Cancer 2024; 23:120. [PMID: 38831402 PMCID: PMC11149191 DOI: 10.1186/s12943-024-02034-7] [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: 11/22/2023] [Accepted: 05/28/2024] [Indexed: 06/05/2024] Open
Abstract
The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.
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Affiliation(s)
- Xiaohang Qiao
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Sabina Y van der Zanden
- Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Xiaoyang Li
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minkang Tan
- Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Yunxiang Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ji-Ying Song
- Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Merle A van Gelder
- Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Feija L Hamoen
- Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Lennert Janssen
- Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Charlotte L Zuur
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Baoxu Pang
- Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Olaf van Tellingen
- Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Junmin Li
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Wuxi Branch of Ruijin Hospital, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai , 200025, China.
| | - Jacques Neefjes
- Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Leiden, The Netherlands.
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20
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Dehghankhold M, Ahmadi F, Nezafat N, Abedi M, Iranpour P, Dehghanian A, Koohi-Hosseinabadi O, Akbarizadeh AR, Sobhani Z. A versatile theranostic magnetic polydopamine iron oxide NIR laser-responsive nanosystem containing doxorubicin for chemo-photothermal therapy of melanoma. BIOMATERIALS ADVANCES 2024; 159:213797. [PMID: 38368693 DOI: 10.1016/j.bioadv.2024.213797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/20/2024]
Abstract
Theranostics nanoparticles (NPs) have recently received much attention in cancer imaging and treatment. This study aimed to develop a multifunctional nanosystem for the targeted delivery of photothermal and chemotherapy agents. Fe3O4 NPs were modified with polydopamine, bovine serum albumin, and loaded with DOX via a thermal-cleavable Azo linker (Fe3O4@PDA@BSA-DOX). The size of Fe3O4@PDA@BSA NPs was approximately 98 nm under the desired conditions. Because of the ability of Fe3O4 and PDA to convert light into heat, the temperature of Fe3O4@PDA@BSA NPs increased to approximately 47 °C within 10 min when exposed to an 808 nm NIR laser with a power density of 1.5 W/cm2. The heat generated by the NIR laser leads to the breaking of AZO linker and drug release. In vivo and in vitro results demonstrated that prepared NPs under laser irradiation successfully eradicated tumor cells without any significant toxicity effect. Moreover, the Fe3O4@PDA@BSA NPs exhibited the potential to function as a contrasting agent. These NPs could accumulate in tumors with the help of an external magnet, resulting in a significant enhancement in the quality of magnetic resonance imaging (MRI). The prepared novel multifunctional NPs seem to be an efficient system for imaging and combination therapy in melanoma.
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Affiliation(s)
- Mahvash Dehghankhold
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Ahmadi
- Research Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Navid Nezafat
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehdi Abedi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooya Iranpour
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirreza Dehghanian
- Molecular Pathology and Cytogenetics Division, Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Amin Reza Akbarizadeh
- Drug and Food Control Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Sobhani
- Research Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran; Drug and Food Control Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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21
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Abdel-Megeed RM, Ghanem HZ, Kadry MO. Alleviation of doxorubicin adverse effects via loading into various drug-delivery systems: a comparative study. Ther Deliv 2024; 15:413-426. [PMID: 38639647 PMCID: PMC11285276 DOI: 10.4155/tde-2023-0121] [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: 11/22/2023] [Accepted: 03/20/2024] [Indexed: 04/20/2024] Open
Abstract
Aim: Drug resistance is still a significant barrier to effective hepatocellular carcinoma therapy. Address the issue of doxorubicin resistance and inter-receptor crosstalk various doxorubicin formulations were investigated. Methods: Hepatocellular carcinoma was carried out using 3-methylechloroanthrene. Animals were then treated with doxorubicin, liposomal doxorubicin, titanium-loaded doxorubicin (TiO2-Dox), lactoferrin-doxorubicin and PEGylated doxorubicin. Biochemical and molecular analyses were assessed. Results: Results have declared a significant alternation of both sodium and potassium concentrations upon 3-methylechloroanthrene administration. Arginase-I and α-L-Fucodinase tumor biomarkers were significantly elevated. C-myc, Hprt-1 and EGFR gene expression were over-expressed. Treatment with the aforementioned treatment regimens significantly modulated all measured parameters. Conclusion: TiO2-Dox, doxorubicin-lactoferrin and PEGylated doxorubicin could be a promising regimen in hepatocellular carcinoma and overcoming the problem of drug resistance.
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Affiliation(s)
- Rehab M Abdel-Megeed
- Therapeutic Chemistry Department, Pharmaceutical & Drug Industries Research Institute, National Research Center, El Buhouth St, Dokki, Cairo, 12622, Egypt
| | - Hassan Z Ghanem
- Therapeutic Chemistry Department, Pharmaceutical & Drug Industries Research Institute, National Research Center, El Buhouth St, Dokki, Cairo, 12622, Egypt
| | - Mai O Kadry
- Therapeutic Chemistry Department, Pharmaceutical & Drug Industries Research Institute, National Research Center, El Buhouth St, Dokki, Cairo, 12622, Egypt
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22
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Agostini M, Traldi P, Hamdan M. Mass Spectrometry Investigation of Some ATP-Binding Cassette (ABC) Proteins. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:200. [PMID: 38399488 PMCID: PMC10890348 DOI: 10.3390/medicina60020200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 02/25/2024]
Abstract
Drug resistance remains one of the main causes of poor outcome in cancer therapy. It is also becoming evident that drug resistance to both chemotherapy and to antibiotics is driven by more than one mechanism. So far, there are at least eight recognized mechanisms behind such resistance. In this review, we choose to discuss one of these mechanisms, which is known to be partially driven by a class of transmembrane proteins known as ATP-binding cassette (ABC) transporters. In normal tissues, ABC transporters protect the cells from the toxic effects of xenobiotics, whereas in tumor cells, they reduce the intracellular concentrations of anticancer drugs, which ultimately leads to the emergence of multidrug resistance (MDR). A deeper understanding of the structures and the biology of these proteins is central to current efforts to circumvent resistance to both chemotherapy, targeted therapy, and antibiotics. Understanding the biology and the function of these proteins requires detailed structural and conformational information for this class of membrane proteins. For many years, such structural information has been mainly provided by X-ray crystallography and cryo-electron microscopy. More recently, mass spectrometry-based methods assumed an important role in the area of structural and conformational characterization of this class of proteins. The contribution of this technique to structural biology has been enhanced by its combination with liquid chromatography and ion mobility, as well as more refined labelling protocols and the use of more efficient fragmentation methods, which allow the detection and localization of labile post-translational modifications. In this review, we discuss the contribution of mass spectrometry to efforts to characterize some members of the ATP-binding cassette (ABC) proteins and why such a contribution is relevant to efforts to clarify the link between the overexpression of these proteins and the most widespread mechanism of chemoresistance.
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Affiliation(s)
| | - Pietro Traldi
- Corso Stati Uniti 4, Istituto di Ricerca Pediatrica Città della Speranza, 35100 Padova, Italy; (M.A.)
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Rodrigues P, Bangali H, Hammoud A, Mustafa YF, Al-Hetty HRAK, Alkhafaji AT, Deorari MM, Al-Taee MM, Zabibah RS, Alsalamy A. COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers. Med Oncol 2024; 41:41. [PMID: 38165473 DOI: 10.1007/s12032-023-02256-7] [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: 10/11/2023] [Accepted: 11/15/2023] [Indexed: 01/03/2024]
Abstract
Cyclooxygenase (COX) enzymes are pivotal in inflammation and cancer development. COX-2, in particular, has been implicated in tumor growth, angiogenesis, and immune evasion. Recently, COX-2 inhibitors have arisen as potential therapeutic agents in cancer treatment. In addition, combining COX inhibitors with other treatment modalities has demonstrated the potential to improve therapeutic efficacy. This review aims to investigate the effects of COX inhibition, both alone and in combination with other methods, on signaling pathways and carcinogenesis in various cancers. In this study, a literature search of all major academic databases was conducted (PubMed, Scholar google), including the leading research on the mechanisms of COX-2, COX-2 inhibitors, monotherapy with COX-2 inhibitors, and combining COX-2-inhibitors with chemotherapeutic agents in tumors. The study encompasses preclinical and clinical evidence, highlighting the positive findings and the potential implications for clinical practice. According to preclinical studies, multiple signaling pathways implicated in tumor cell proliferation, survival, invasion, and metastasis can be suppressed by inhibiting COX. In addition, combining COX inhibitors with chemotherapy drugs, targeted therapies, immunotherapies, and miRNA-based approaches has enhanced anti-tumor activity. These results suggest that combination therapy has the potential to overcome resistance mechanisms and improve treatment outcomes. However, caution must be exercised when selecting and administering combination regimens. Not all combinations of COX-2 inhibitors with other drugs result in synergistic effects; some may even have unfavorable interactions. Therefore, personalized approaches that consider the specific characteristics of the cancer and the medications involved are crucial for optimizing therapeutic strategies. In conclusion, as monotherapy or combined with other methods, COX inhibition bears promise in modulating signaling pathways and inhibiting carcinogenesis in various cancers. Additional studies and well-designed clinical trials are required to completely elucidate the efficacy of COX inhibition and combination therapy in enhancing cancer treatment outcomes. This narrative review study provides a detailed summary of COX-2 monotherapy and combination targeted therapy in cancer treatment.
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Affiliation(s)
- Paul Rodrigues
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Asir-Abha, Kingdom of Saudi Arabia
| | - Harun Bangali
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Asir-Abha, Kingdom of Saudi Arabia
| | - Ahmad Hammoud
- Department of Medical and Technical Information Technology, Bauman Moscow State Technical University, Moscow, Russia.
- Department of Mathematics and Natural Sciences, Gulf University for Science and Technology, Mishref Campus, Mubarak Al-Abdullah, Kuwait.
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | | | | | - Maha Medha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | | | - Rahman S Zabibah
- College of Medical Technique, the Islamic University, Najaf, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
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Amoyav B, Bloom AI, Goldstein Y, Miller R, Sharam M, Fluksman A, Benny O. Drug-Eluting Porous Embolic Microspheres for Trans-Arterial Delivery of Dual Synergistic Anticancer Therapy for the Treatment of Liver Cancer. Adv Healthc Mater 2023; 12:e2301548. [PMID: 37315950 PMCID: PMC11469112 DOI: 10.1002/adhm.202301548] [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: 05/12/2023] [Indexed: 06/16/2023]
Abstract
Blockage of blood supply while administering chemotherapy to tumors, using trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and advanced-stage unresectable Hepatocellular carcinoma (HCC). However, HCC is characterized by a poor prognosis and high recurrence rates (≈30%), partly due to a hypoxic pro-angiogenic and pro-cancerous microenvironment. This study investigates how modifying tissue stress while improving drug exposure in target organs may maximize the therapeutic outcomes. Porous degradable polymeric microspheres (MS) are designed to obtain a gradual occlusion of the hepatic artery that nourishes the liver, while enabling efficient drug perfusion to the tumor site. The fabricated porous MS are introduced intrahepatically and designed to release a combination therapy of Doxorubicin (DOX) and Tirapazamine (TPZ), which is a hypoxia-activated prodrug. Liver cancer cell lines that are treated with the combination therapy under hypoxia reveal a synergic anti-proliferation effect. An orthotopic liver cancer model, based on N1-S1 hepatoma in rats, is used for the efficacy, biodistribution, and safety studies. Porous DOX-TPZ MS are very effective in suppressing tumor growth in rats, and induction tissue necrosis is associated with high intratumor drug concentrations. Porous particles without drugs show some advantages over nonporous particles, suggesting that morphology may affect the treatment outcomes.
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Affiliation(s)
- Benzion Amoyav
- The Institute for Drug ResearchSchool of PharmacyThe Faculty of MedicineThe Hebrew University of JerusalemJerusalem91120Israel
| | - Allan I. Bloom
- Department of Medical Imaging‐Interventional RadiologyHadassah Medical CenterJerusalem911200Israel
| | - Yoel Goldstein
- The Institute for Drug ResearchSchool of PharmacyThe Faculty of MedicineThe Hebrew University of JerusalemJerusalem91120Israel
| | - Rafael Miller
- Department of General SurgeryKaplan Medical CenterAffiliated to Hebrew University JerusalemRehovot76100Israel
| | - Mariana Sharam
- Authority for Biological and Biomedical ModelsHadassah Medical CenterJerusalem911200Israel
| | - Arnon Fluksman
- The Institute for Drug ResearchSchool of PharmacyThe Faculty of MedicineThe Hebrew University of JerusalemJerusalem91120Israel
| | - Ofra Benny
- The Institute for Drug ResearchSchool of PharmacyThe Faculty of MedicineThe Hebrew University of JerusalemJerusalem91120Israel
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Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G. Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming. Mol Aspects Med 2023; 93:101205. [PMID: 37515939 DOI: 10.1016/j.mam.2023.101205] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/15/2023] [Accepted: 07/17/2023] [Indexed: 07/31/2023]
Abstract
Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance.
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Affiliation(s)
- Roberto Mattioli
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy
| | - Beatrice Colotti
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Luciana Mosca
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy.
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Mitchell MI, Loudig O. Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis. Biomedicines 2023; 11:2534. [PMID: 37760975 PMCID: PMC10526527 DOI: 10.3390/biomedicines11092534] [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: 06/16/2023] [Revised: 08/30/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
Human tumors are increasingly being described as a complex "ecosystem", that includes many different cell types, secreted growth factors, extracellular matrix (ECM) components, and microvessels, that altogether create the tumor microenvironment (TME). Within the TME, epithelial cancer cells control the function of surrounding stromal cells and the non-cellular ECM components in an intricate orchestra of signaling networks specifically designed for cancer cells to exploit surrounding cells for their own benefit. Tumor-derived extracellular vesicles (EVs) released into the tumor microenvironment are essential mediators in the reprogramming of surrounding stromal cells, which include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor endothelial cells (TECs), which are responsible for the promotion of neo-angiogenesis, immune cell evasion, and invasion which are essential for cancer progression. Perhaps most importantly, tumor-derived EVs play critical roles in the metastatic dissemination of tumor cells through their two-fold role in initiating cancer cell invasion and the establishment of the pre-metastatic niche, both of which are vital for tumor cell migration, homing, and colonization at secondary tumor sites. This review discusses extracellular vesicle trafficking within the tumor microenvironment and pre-metastatic niche formation, focusing on the complex role that EVs play in orchestrating cancer-to-stromal cell communication in order to promote the metastatic dissemination of cancer cells.
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Affiliation(s)
| | - Olivier Loudig
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA;
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Ghionescu AV, Sorop A, Dima SO. The pivotal role of EMT-related noncoding RNAs regulatory axes in hepatocellular carcinoma. Front Pharmacol 2023; 14:1270425. [PMID: 37767397 PMCID: PMC10520284 DOI: 10.3389/fphar.2023.1270425] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major health problem worldwide, being the leading cause of cancer-related deaths, with limited treatment options, especially in its advanced stages. Tumor resistance is closely associated with the activation of the EMT phenomenon and its reversal, being modulated by different molecules, including noncoding RNAs (ncRNAs). Noncoding RNAs have the potential to function as both tumor suppressors and oncogenic molecules, controlling the malignant potential of HCC cells. Basically, these molecules circulate in the tumor microenvironment, encapsulated in exosomes. Their impact on cell biology is more significant than originally expected, which makes related research rather complex. The temporal and spatial expression patterns, precise roles and mechanisms of specific ncRNAs encapsulated in exosomes remain primarily unknown in different stages of the disease. This review aims to highlight the recent advances in ncRNAs related to EMT and classifies the described mechanism as direct and indirect, for a better summarization. Moreover, we provide an overview of current research on the role of ncRNAs in several drug resistance-related pathways, including the emergence of resistance to sorafenib, doxorubicin, cisplatin and paclitaxel therapy. Nevertheless, we comprehensively discuss the underlying regulatory mechanisms of exosomal ncRNAs in EMT-HCC via intercellular communication pathways.
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Affiliation(s)
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Lo Dico A, Martelli C, Corsi F, Porro D, Ottobrini L, Bertoli G. CMA mediates resistance in breast cancer models. Cancer Cell Int 2023; 23:133. [PMID: 37407979 PMCID: PMC10324152 DOI: 10.1186/s12935-023-02969-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/10/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker. METHODS A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA. RESULTS In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours. CONCLUSION Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.
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Affiliation(s)
- Alessia Lo Dico
- Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Milan, Italy
- NBFC, National Biodiversity Future Center, Palermo, Italy
| | - C Martelli
- Department of Pathophysiology and Transplantation, University of Milan, Segrate, Milan, Italy
| | - F Corsi
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Surgery Department, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - D Porro
- Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Milan, Italy
- NBFC, National Biodiversity Future Center, Palermo, Italy
| | - L Ottobrini
- Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Milan, Italy.
- Department of Pathophysiology and Transplantation, University of Milan, Segrate, Milan, Italy.
| | - G Bertoli
- Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Milan, Italy.
- NBFC, National Biodiversity Future Center, Palermo, Italy.
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Zlotnikov ID, Dobryakova NV, Ezhov AA, Kudryashova EV. Achievement of the Selectivity of Cytotoxic Agents against Cancer Cells by Creation of Combined Formulation with Terpenoid Adjuvants as Prospects to Overcome Multidrug Resistance. Int J Mol Sci 2023; 24:ijms24098023. [PMID: 37175727 PMCID: PMC10178335 DOI: 10.3390/ijms24098023] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/20/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Oncological diseases are difficult to treat even with strong drugs due to development the multidrug resistance (MDR) of cancer cells. A strategy is proposed to increase the efficiency and selectivity of cytotoxic agents against cancer cells to engage the differences in the morphology and microenvironment of tumor and healthy cells, including the pH, membrane permeability, and ion channels. Using this approach, we managed to develop enhanced formulations of cytotoxic agents with adjuvants (which are known as efflux inhibitors and as ion channel inhibitors in tumors)-with increased permeability in A549 and a protective effect on healthy HEK293T cells. The composition of the formulation is as follows: cytotoxic agents (doxorubicin (Dox), paclitaxel (Pac), cisplatin) + adjuvants (allylbenzenes and terpenoids) in the form of inclusion complexes with β-cyclodextrin. Modified cyclodextrins make it possible to obtain soluble forms of pure substances of the allylbenzene and terpenoid series and increase the solubility of cytotoxic agents. A comprehensive approach based on three methods for studying the interaction of drugs with cells is proposed: MTT test-quantitative identification of surviving cells; FTIR spectroscopy-providing information on the molecular mechanisms inaccessible to study by any other methods (including binding to DNA, surface proteins, or lipid membrane); confocal microscopy for the visualization of observed effects of Dox accumulation in cancer or healthy cells depending on the drug formulation as a direct control of the correctness of interpretation of the results obtained by the two other methods. We found that eugenol (EG) and apiol increase the intracellular concentration of cytostatic in A549 cells by 2-4 times and maintain it for a long time. However, an important aspect is the selectivity of the enhancing effect of adjuvants on tumor cells in relation to healthy ones. Therefore, the authors focused on adjuvant's effect on the control healthy cells (HEK293T): EG and apiol demonstrate "protective" properties from cytostatic penetration by reducing intracellular concentrations by about 2-3 times. Thus, a combined formulation of cytostatic drugs has been found, showing promise in the aspects of improving the efficiency and selectivity of antitumor drugs; thereby, one of the perspective directions for overcoming MDR is suggested.
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Affiliation(s)
- Igor D Zlotnikov
- Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
| | - Natalia V Dobryakova
- Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
| | - Alexander A Ezhov
- Faculty of Physics, Lomonosov Moscow State University, Leninskie Gory 1/2, 119991 Moscow, Russia
| | - Elena V Kudryashova
- Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
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30
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Mukherjee S, Bhatti GK, Chhabra R, Reddy PH, Bhatti JS. Targeting mitochondria as a potential therapeutic strategy against chemoresistance in cancer. Biomed Pharmacother 2023; 160:114398. [PMID: 36773523 DOI: 10.1016/j.biopha.2023.114398] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/21/2023] [Accepted: 02/08/2023] [Indexed: 02/11/2023] Open
Abstract
The importance of mitochondria is not only limited to energy generation but also in several physical and chemical processes critical for cell survival. Mitochondria play an essential role in cellular apoptosis, calcium ion transport and cellular metabolism. Mutation in the nuclear and mitochondrial genes, altered oncogenes/tumor suppressor genes, and deregulated signalling for cell viability are major reasons for cancer progression and chemoresistance. The development of drug resistance in cancer patients is a major challenge in cancer treatment as the resistant cells are often more aggressive. The drug resistant cells of numerous cancer types exhibit the deregulation of mitochondrial function. The increased biogenesis of mitochondria and its dynamic alteration contribute to developing resistance. Further, a small subpopulation of cancer stem cells in the heterogeneous tumor is primarily responsible for chemoresistance and has an attribute of mitochondrial dysfunction. This review highlights the critical role of mitochondrial dysfunction in chemoresistance in cancer cells through the processes of apoptosis, autophagy/mitophagy, and cancer stemness. Mitochondria-targeted therapeutic strategies might help reduce cancer progression and chemoresistance induced by various cancer drugs.
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Affiliation(s)
- Soumi Mukherjee
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India.
| | - Ravindresh Chhabra
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, India.
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience and Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
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Seydi H, Nouri K, Rezaei N, Tamimi A, Hassan M, Mirzaei H, Vosough M. Autophagy orchestrates resistance in hepatocellular carcinoma cells. Biomed Pharmacother 2023; 161:114487. [PMID: 36963361 DOI: 10.1016/j.biopha.2023.114487] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/26/2023] Open
Abstract
Treatment resistance is one of the major barriers for therapeutic strategies in hepatocellular carcinoma (HCC). Many studies have indicated that chemotherapy and radiotherapy induce autophagy machinery (cell protective autophagy) in HCC cells. In addition, many experiments report a remarkable crosstalk between treatment resistance and autophagy pathways. Thus, autophagy could be one of the key factors enabling tumor cells to hinder induced cell death after medical interventions. Therefore, extensive research on the molecular pathways involved in resistance induction and autophagy have been conducted to achieve the desired therapeutic response. The key molecular pathways related to the therapy resistance are TGF-β, MAPK, NRF2, NF-κB, and non-coding RNAs. In addition, EMT, drug transports, apoptosis evasion, DNA repair, cancer stem cells, and hypoxia could have considerable impact on the hepatoma cell's response to therapies. These mechanisms protect tumor cells against various treatments and many studies have shown that each of them is connected to the molecular pathways of autophagy induction in HCC. Hence, autophagy inhibition may be an effective strategy to improve therapeutic outcome in HCC patients. In this review, we further highlight how autophagy leads to poor response during treatment through a complex molecular network and how it enhances resistance in primary liver cancer. We propose that combinational regimens of approved HCC therapeutic protocols plus autophagy inhibitors may overcome drug resistance in HCC therapy.
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Affiliation(s)
- Homeyra Seydi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Kosar Nouri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Niloufar Rezaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Department of Biotechnology, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Islamic Republic of Iran
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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Doxorubicin and Cisplatin Modulate miR-21, miR-106, miR-126, miR-155 and miR-199 Levels in MCF7, MDA-MB-231 and SK-BR-3 Cells That Makes Them Potential Elements of the DNA-Damaging Drug Treatment Response Monitoring in Breast Cancer Cells—A Preliminary Study. Genes (Basel) 2023; 14:genes14030702. [PMID: 36980974 PMCID: PMC10048428 DOI: 10.3390/genes14030702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/08/2023] [Accepted: 03/09/2023] [Indexed: 03/16/2023] Open
Abstract
One of the most innovative medical trends is personalized therapy, based on simple and reproducible methods that detect unique features of cancer cells. One of the good prognostic and diagnostic markers may be the miRNA family. Our work aimed to evaluate changes in selected miRNA levels in various breast cancer cell lines (MCF7, MDA-MB-231, SK-BR-3) treated with doxorubicin or cisplatin. The selection was based on literature data regarding the most commonly altered miRNAs in breast cancer (21-3p, 21-5p, 106a-5p, 126-3p, 126-5p, 155-3p, 155-5p, 199b-3p, 199b-5p, 335-3p, 335-5p). qPCR assessment revealed significant differences in the basal levels of some miRNAs in respective cell lines, with the most striking difference in miR-106a-5p, miR-335-5p and miR-335-3p—all of them were lowest in MCF7, while miR-153p was not detected in SK-BR-3. Additionally, different alterations of selected miRNAs were observed depending on the cell line and the drug. However, regardless of these variables, 21-3p/-5p, 106a, 126-3p, 155-3p and 199b-3p miRNAs were shown to respond either to doxorubicin or to cisplatin treatment. These miRNAs seem to be good candidates for markers of breast cancer cell response to doxorubicin or cisplatin. Especially since some earlier reports suggested their role in affecting pathways and expression of genes associated with the DNA-damage response. However, it must be emphasized that the preliminary study shows effects that may be highly related to the applied drug itself and its concentration. Thus, further examination, including human samples, is required.
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Li CJ, Tsai HW, Chen YL, Wang CI, Lin YH, Chu PM, Chi HC, Huang YC, Chen CY. Cisplatin or Doxorubicin Reduces Cell Viability via the PTPIVA3-JAK2-STAT3 Cascade in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:123-138. [PMID: 36741246 PMCID: PMC9896975 DOI: 10.2147/jhc.s385238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/29/2022] [Indexed: 02/01/2023] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) accounts for 80% of all liver cancers and is the 2nd leading cause of cancer-related death in Taiwan. Various factors, including rapid cell growth, a high recurrence rate and drug resistance, make HCC difficult to cure. Moreover, the survival rate of advanced HCC patients treated with systemic chemotherapy remains unsatisfactory. Hence, the identification of novel molecular targets and the underlying mechanisms of chemoresistance in HCC and the development more effective therapeutic regimens are desperately needed. Methods An MTT assay was used to determine the cell viability after cisplatin or doxorubicin treatment. Western blotting, qRT‒PCR and immunohistochemistry were utilized to examine the protein tyrosine phosphatase IVA3 (PTP4A3) level and associated signaling pathways. ELISA was utilized to analyze the levels of the inflammatory cytokine IL-6 influenced by cisplatin, doxorubicin and PTP4A3 silencing. Results In this study, we found that PTP4A3 in the cisplatin/doxorubicin-resistant microarray was closely associated with the overall and recurrence-free survival rates of HCC patients. Cisplatin or doxorubicin significantly reduced cell viability and decreased PTP4A3 expression in hepatoma cells. IL-6 secretion increased with cisplatin or doxorubicin treatment and after PTP4A3 silencing. Furthermore, PTP4A3 was highly expressed in tumor tissues versus adjacent normal tissues from HCC patients. In addition, we evaluated the IL-6-associated signaling pathway involving STAT3 and JAK2, and the levels of p-STAT3, p-JAK2, STAT3 and JAK2 were obviously reduced with cisplatin or doxorubicin treatment in HCC cells using Western blotting and were also decreased after silencing PTP4A3. Collectively, we suggest that cisplatin or doxorubicin decreases HCC cell viability via downregulation of PTP4A3 expression through the IL-6R-JAK2-STAT3 cascade. Discussion Therefore, emerging evidence provides a deep understanding of the roles of PTP4A3 in HCC cisplatin/doxorubicin chemoresistance, which can be applied to develop early diagnosis strategies and reveal prognostic factors to establish novel targeted therapeutics to specifically treat HCC.
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Affiliation(s)
- Chao-Jen Li
- Department of General & Gastroenterological Surgery, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Li Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-I Wang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Pei-Ming Chu
- Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung, Taiwan,Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsiang-Cheng Chi
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Yi-Ching Huang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan,Correspondence: Cheng-Yi Chen, Tel/Fax +886-6-2353535#5329, Email
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Hamed AR, Yahya SMM, Nabih HK. Anti-drug resistance, anti-inflammation, and anti-proliferation activities mediated by melatonin in doxorubicin-resistant hepatocellular carcinoma: in vitro investigations. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1117-1128. [PMID: 36651944 DOI: 10.1007/s00210-023-02385-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is the major life-threatening primary liver malignancy in both sexes all over the world. Unfortunately, the majority of patients are diagnosed at later stages because HCC does not elicit obvious symptoms during its early incidence. Consequently, most individuals escape the first-line HCC treatments and are treated with chemotherapy. Regrettably, the therapeutic outcomes for those patients are usually poor because of the development of multidrug resistance phenomena. Furthermore, most anti-HCC therapies cause severe undesired side effects that notably interfere with the life quality of such patients. Accordingly, there is an important need to search for an alternative therapeutic drug or adjuvant which is more efficient with safe or even minimal side effects for HCC treatment. Melatonin was recently reported to exert intrinsic antitumor activity in different cancers. However, the regulatory pathways underlying the antitumor activity of melatonin are poorly understood in resistant liver cells. Furthermore, a limited number of studies have addressed the therapeutic role of melatonin in HCC cells resistant to doxorubicin chemotherapy. In this study, we investigated the antitumor effects of melatonin in doxorubicin-resistant HepG2 cells and explored the regulatory pivotal targets underlying these effects. To achieve our aim, an MTT assay was used to calculate the 50% inhibitory concentration of melatonin and evaluate its antiproliferative effect on resistant cells. Additionally, qRT-PCR was used to quantify genes having a role in drug resistance phenotype (ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2); apoptosis (caspases-3, and -7, Bcl2, Bax, and p53); anti-oxidation (NRF2); expression of melatonin receptors (MT1, MT2, and MT3); besides, programmed death receptor PD-1 gene. The active form of the caspase-3 enzyme was estimated by ELISA. A human inflammatory antibody membrane array was employed to quantify forty inflammatory factors expressed in treated cells. We observed that melatonin inhibited the proliferation of doxorubicin-resistant HepG2 cells in a dose-dependent manner after 24-h incubation time with a calculated IC50 greater than 10 mM (13.4 mM), the expression levels of genes involved in drug resistance response (ABCB1, ABCC1, ABCC5, and ABCG2) were downregulated. Also, the expression of caspase-3, Caspase-7, NRF2, and p53 genes were expressed at higher levels as compared to control (DMSO-treated cells). An active form of caspase-3 was confirmed by ELISA. Moreover, the anti-inflammatory effect of melatonin was detected through the calculated fold change to control which was reduced for various mediators that have a role in the inflammation pathway. The current findings introduce melatonin as a promising anti-cancer treatment for human-resistant HCC which could be used in combination with current chemotherapeutic regimens to improve the outcome and reduce the developed multidrug resistance.
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Affiliation(s)
- Ahmed R Hamed
- Chemistry of Medicinal Plants Department, and Biology Unit, Central Laboratory for Pharmaceutical and Drug Industries Research Institute, National Research Centre, 33 El-Bohouth St, Dokki, Giza, 12622, Egypt
| | - Shaymaa M M Yahya
- Hormones Department, Medicine and Clinical Studies Research Institute, and Stem Cell Lab, Centre of Excellence for Advanced Sciences, National Research Centre, 33 El-Bohouth St, Dokki, Giza, 12622, Egypt
| | - Heba K Nabih
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, 33 El-Bohouth St, Dokki, Giza, 12622, Egypt.
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35
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Eljack S, David S, Faggad A, Chourpa I, Allard-Vannier E. Nanoparticles design considerations to co-deliver nucleic acids and anti-cancer drugs for chemoresistance reversal. Int J Pharm X 2022; 4:100126. [PMID: 36147518 PMCID: PMC9486027 DOI: 10.1016/j.ijpx.2022.100126] [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] [Received: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 12/24/2022] Open
Abstract
Chemoresistance and hence the consequent treatment failure is considerably challenging in clinical cancer therapeutics. The understanding of the genetic variations in chemoresistance acquisition encouraged the use of gene modulatory approaches to restore anti-cancer drug efficacy. Many smart nanoparticles are designed and optimized to mediate combinational therapy between nucleic acid and anti-cancer drugs. This review aims to define a rational design of such co-loaded nanocarriers with the aim of chemoresistance reversal at various cellular levels to improve the therapeutic outcome of anticancer treatment. Going through the principles of therapeutics loading, physicochemical characteristics tuning, and different nanocarrier modifications, also looking at combination effectiveness on chemosensitivity restoration. Up to now, these emerging nanocarriers are in development status but are expected to introduce outstanding outcomes.
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36
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Gul S, Maqbool MF, Maryam A, Khan M, Shakir HA, Irfan M, Ara C, Li Y, Ma T. Vitamin K: A novel cancer chemosensitizer. Biotechnol Appl Biochem 2022; 69:2641-2657. [PMID: 34993998 DOI: 10.1002/bab.2312] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 12/24/2021] [Indexed: 12/27/2022]
Abstract
Cancer incidences are growing rapidly and causing millions of deaths globally. Cancer treatment is one of the most exigent challenges. Drug resistance is a natural phenomenon and is considered one of the major obstacles in the successful treatment of cancer by chemotherapy. Combination therapy by the amalgamation of various anticancer drugs has suggested modulating tumor response by targeting various signaling pathways in a synergistic or additive manner. Vitamin K is an essential nutrient and has recently been investigated as a potential anticancer agent. The combination of vitamin K analogs, such as vitamins K1, K2, K3, and K5, with other chemotherapeutic drugs have demonstrated a safe, cost-effective, and most efficient way to overcome drug resistance and improved the outcomes of prevailing chemotherapy. Published reports have shown that vitamin K in combination therapy improved the efficacy of clinical drugs by promoting apoptosis and cell cycle arrest and overcoming drug resistance by inhibiting P-glycoprotein. In this review, we discuss the mechanism, cellular targets, and possible ways to develop vitamin K subtypes into effective cancer chemosensitizers. Finally, this review will provide a scientific basis for exploiting vitamin K as a potential agent to improve the efficacy of chemotherapeutic drugs.
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Affiliation(s)
- Sameena Gul
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Cancer Research Lab, Institute of Zoology, University of the Punjab, Quaid-e-Azam Campus Lahore, Lahore, Pakistan
| | - Muhammad Faisal Maqbool
- Cancer Research Lab, Institute of Zoology, University of the Punjab, Quaid-e-Azam Campus Lahore, Lahore, Pakistan
| | - Amara Maryam
- Cancer Research Lab, Institute of Zoology, University of the Punjab, Quaid-e-Azam Campus Lahore, Lahore, Pakistan
| | - Muhammad Khan
- Cancer Research Lab, Institute of Zoology, University of the Punjab, Quaid-e-Azam Campus Lahore, Lahore, Pakistan
| | - Hafiz Abdullah Shakir
- Cancer Research Lab, Institute of Zoology, University of the Punjab, Quaid-e-Azam Campus Lahore, Lahore, Pakistan
| | - Muhammad Irfan
- Department of Biotechnology, University of Sargodha, Sargodha, Pakistan
| | - Chaman Ara
- Cancer Research Lab, Institute of Zoology, University of the Punjab, Quaid-e-Azam Campus Lahore, Lahore, Pakistan
| | - Yongming Li
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Tonghui Ma
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Pugh L, Pancholi A, Purat PC, Agudo-Alvarez S, Benito-Arenas R, Bastida A, Bolanos-Garcia VM. Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer. Int J Mol Sci 2022; 23:ijms232214228. [PMID: 36430712 PMCID: PMC9692432 DOI: 10.3390/ijms232214228] [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: 10/17/2022] [Revised: 11/11/2022] [Accepted: 11/13/2022] [Indexed: 11/19/2022] Open
Abstract
The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in the catalytic activity and the transcription regulation of Mps1 are associated with genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and frameshift mutations have been reported in a wide range of types of cancer of different tissue origin. Due to these features, Mps1 arises as one promising drug target for cancer therapy. In this contribution, we developed a computational biology approach to study the dynamics of human Mps1 kinase interaction with isoflavones, a class of natural flavonoids, and compared their predicted mode of binding with that observed in the crystal structure of Mps1 in complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We concluded that isoflavones define a chemical scaffold that can be used to develop new Mps1 inhibitors for the treatment of cancer associated with Mps1 amplification and aberrant chromosome segregation. In a broader context, the present report illustrates how modern chemoinformatics approaches can accelerate drug development in oncology.
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Affiliation(s)
- Lauren Pugh
- Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UK
| | - Alisha Pancholi
- Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UK
| | - Priscila Celeste Purat
- Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UK
| | - Sandra Agudo-Alvarez
- Departamento de Química Bio-Orgánica, IQOG, c/Juan de la Cierva 3, E-28006 Madrid, Spain
| | - Raúl Benito-Arenas
- Departamento de Química Bio-Orgánica, IQOG, c/Juan de la Cierva 3, E-28006 Madrid, Spain
| | - Agatha Bastida
- Departamento de Química Bio-Orgánica, IQOG, c/Juan de la Cierva 3, E-28006 Madrid, Spain
- Correspondence: (A.B.); (V.M.B.-G.); Tel.: +44-01865-484146 (V.M.B.-G.)
| | - Victor M. Bolanos-Garcia
- Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UK
- Correspondence: (A.B.); (V.M.B.-G.); Tel.: +44-01865-484146 (V.M.B.-G.)
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Doxorubicin resistant choriocarcinoma cell line derived spheroidal cells exhibit stem cell markers but reduced invasion. 3 Biotech 2022; 12:184. [PMID: 35875180 PMCID: PMC9300786 DOI: 10.1007/s13205-022-03243-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 06/25/2022] [Indexed: 11/06/2022] Open
Abstract
Cell cycle-specific cancer chemotherapy is based on the ability of a drug to halt, minimise or destroy rapidly dividing cells. However, their efficacy is limited by the emergence of a self-renewing cell pool called “cancer stem cells” (CSC). Choriocarcinoma is a tumour of trophoblastic tissue. We, in this study, analysed whether spheroids generated from doxorubicin-treated and non-treated choriocarcinoma cell lines exhibit markers of stem cells. Two choriocarcinoma cell lines, namely JEG-3 and BeWo, were used in this study. Spheroids were generated from doxorubicin-treated cells and the non-treated cells under non-adherent condition, followed by analysis of stem-cell markers’ expression, namely NANOG, OCT4 and SOX2. Immunofluorescence analysis suggested a general increase in the markers’ concentration in spheroids relative to the parental cells. RT-qPCR and immunoblots showed an increase in the stem-cell marker expression in spheroids generated from doxorubicin-treated when compared to non-treated cells. In spheroids, Sox2 was significantly upregulated in doxorubicin-treated spheroids, whereas Nanog and Oct4 were generally downregulated when compared to non-treated spheroids. Both 2D and 3D invasion assays showed that the spheroids treated with doxorubicin exhibited reduced invasion. Our data suggest that choriocarcinoma cell lines may have the potential to produce spheroidal cells, yet the drug-treatment affected the invasion potential of spheroids.
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Maashi MS, Al-Mualm M, Al-Awsi GRL, Opulencia MJC, Al-Gazally ME, Abdullaev B, Abdelbasset WK, Ansari MJ, Jalil AT, Alsaikhan F, Shalaby MN, Mustafa YF. Apigenin alleviates resistance to doxorubicin in breast cancer cells by acting on the JAK/STAT signaling pathway. Mol Biol Rep 2022; 49:8777-8784. [PMID: 35804214 DOI: 10.1007/s11033-022-07727-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/14/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Breast cancer is the most frequent cancer among women. Despite the effectiveness of Doxorubicin (DOX) as a chemotherapeutic for the treatment of breast cancer, the therapy-resistance remains unsolvable. Apigenin is a natural dietary flavonoid with potential anticancer activities. Our study's intention was to evaluate the effect of Apigenin on DOX resistance in MCF-7 cells. METHODS DOX-resistant MCF-7 cell line (MCF-7R) was developed by treating MCF-7 cells with increasing concentrations of DOX (0-100 µM). The viability of cell lines was assayed using MTT method. Quantitative polymerase chain reaction method was performed to measure multidrug-resistance 1 (MDR1) gene expression level. The expression of MDR1, Janus kinase 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3) proteins were determined by western blotting. RESULTS MCF-7R cell line showed resistance to DOX in comparison to MCF-7 cells. Apigenin had a significant effect on the reduction of viability of both MCF-7 and MCF-7R cell lines. However, DOX-resistance in the MCF-7 cell line was considerably decreased due to the co-treatment of MCF-7R cells with Apigenin. This natural compound also downregulated the expression of MDR1 at mRNA and protein levels both in resistant and non-resistant cells. Apigenin significantly prohibited the phosphorylation and activation of JAK2 and STAT3 proteins both in MCF-7 and MCF-7R cell lines. CONCLUSIONS The present results suggested, for the first time, Apigenin as an ideal therapeutic for ameliorating DOX resistance in breast cancer. These data also proposed a novel mechanism for the anti-resistance activity of Apigenin by regulating the JAK2/STAT3/MDR1 axis.
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Affiliation(s)
- Marwah Suliman Maashi
- Medical Laboratory Science Department, Faculty of Applied Medical Sciences, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Mahmood Al-Mualm
- Department of Clinical Laboratory Techniques, Al-Nisour University College, Baghdad, Iraq
| | | | | | | | - Bekhzod Abdullaev
- Department of Science and Innovation, AKFA University, Tashkent, Uzbekistan
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj, Saudi Arabia
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, Iraq.
| | - Fahad Alsaikhan
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Kingdom of Saudi Arabia
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
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Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review. Molecules 2022; 27:molecules27144478. [PMID: 35889350 PMCID: PMC9318127 DOI: 10.3390/molecules27144478] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases and deaths are increasing at a rapid rate worldwide. Doxorubicin, an anticancer agent, is currently used to treat several types of cancer. It disrupts myriad processes such as histone eviction, ceramide overproduction, DNA-adduct formation, reactive oxygen species generation, Ca2+, and iron hemostasis regulation. However, its use is limited by factors such as drug resistance, toxicity, and congestive heart failure reported in some patients. The combination of doxorubicin with other chemotherapeutic agents has been reported as an effective treatment option for cancer with few side effects. Thus, the hybridization of doxorubicin and other chemotherapeutic drugs is regarded as a promising approach that can lead to effective anticancer agents. This review gives an update on hybrid compounds containing the scaffolds of doxorubicin and its derivatives with potent chemotherapeutic effects.
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Engle K, Kumar G. Cancer multidrug-resistance reversal by ABCB1 inhibition: A recent update. Eur J Med Chem 2022; 239:114542. [PMID: 35751979 DOI: 10.1016/j.ejmech.2022.114542] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/09/2022] [Accepted: 06/14/2022] [Indexed: 11/04/2022]
Abstract
Chemotherapy is one of the most common treatments for cancer that uses one or more anti-cancer drugs as a part of the standardized chemotherapy regimen. Cytotoxic chemicals delay and prevent cancer cells from multiplying, invading, and metastasizing. However, the significant drawbacks of cancer chemotherapy are the lack of selectivity of the cytotoxic drugs to tumour cells and normal cells and the development of resistance by cells for the particular drug or the combination of drugs. Multidrug resistance (MDR) is the low sensitivity of specific cells against drugs associated with cancer chemotherapy. The most common mechanisms of anticancer drug resistance are: (a) drug-dependent MDR (b) target-dependent MDR, and (c) drug target-independent MDR. In all the factors, the overexpression of multidrug efflux systems contributes significantly to the increased resistance in the cancer cells. Multidrug resistance due to efflux of anticancer drugs by membrane ABC transporters includes ABCB1, ABCC1, and ABCG2. ABCB1 inhibition can restore the sensitivity of the cancerous cells toward chemotherapeutic drugs. In this review, we discussed ABCB1 inhibitors under clinical studies with their mode of action, potency and selectivity. Also, we have highlighted the contribution of repurposing drugs, biologics and nano formulation strategies to combat multidrug resistance by modulating the ABCB1 activity.
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Affiliation(s)
- Kritika Engle
- Department of Natural Products, Chemical Sciences, National Institute of Pharmaceutical Education and Research-Hyderabad, Hyderabad, Balanagar, 500037, India
| | - Gautam Kumar
- Department of Natural Products, Chemical Sciences, National Institute of Pharmaceutical Education and Research-Hyderabad, Hyderabad, Balanagar, 500037, India.
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Lv YF, Deng ZQ, Bi QC, Tang JJ, Chen H, Xie CS, Liang QR, Xu YH, Luo RG, Tang Q. Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin. Drug Deliv 2022; 29:1743-1753. [PMID: 35635315 PMCID: PMC9176673 DOI: 10.1080/10717544.2022.2081384] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.
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Affiliation(s)
- Yang-Feng Lv
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Institute for Advanced Study, Nanchang University, Nanchang, China
| | - Zhi-Qiang Deng
- Department of Oncology, The First People's Hospital of Fuzhou, Fuzhou, China
| | - Qiu-Chen Bi
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Institute for Advanced Study, Nanchang University, Nanchang, China
| | - Jian-Jun Tang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hong Chen
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Chuan-Sheng Xie
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Qing-Rong Liang
- Institute for Advanced Study, Nanchang University, Nanchang, China
| | - Yu-Hua Xu
- Department of Interventional Radiology, Jiangxi Province Chest Hospital, Nanchang, China
| | - Rong-Guang Luo
- Department of Medical Imaging and Interventional Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qun Tang
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Institute for Advanced Study, Nanchang University, Nanchang, China.,Department of Oncology, The First People's Hospital of Fuzhou, Fuzhou, China
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Interaction of M2 macrophages with hepatocellular carcinoma co-culture system in the presence of doxorubicin-loaded nanoparticles. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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LC-MS Profiled Chemical Constituents, Molecular Modeling, and In vitro Bioactivity Evaluations of Suaeda vermiculata Extracts as Anti-Hepatocellular Carcinoma Preparation: Assessment of the Constituents’ Role, and Receptor Docking Feasibility Based Activity Projections. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2022.103950] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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45
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Cha HK, Cheon S, Kim H, Lee KM, Ryu HS, Han D. Discovery of Proteins Responsible for Resistance to Three Chemotherapy Drugs in Breast Cancer Cells Using Proteomics and Bioinformatics Analysis. Molecules 2022; 27:molecules27061762. [PMID: 35335125 PMCID: PMC8954867 DOI: 10.3390/molecules27061762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/19/2022] [Accepted: 03/02/2022] [Indexed: 02/04/2023] Open
Abstract
Chemoresistance is a daunting obstacle to the effective treatment of breast cancer patients receiving chemotherapy. Although the mechanism of chemotherapy drug resistance has been explored broadly, the precise mechanism at the proteome level remains unclear. Especially, comparative studies between widely used anticancer drugs in breast cancer are very limited. In this study, we employed proteomics and bioinformatics approaches on chemoresistant breast cancer cell lines to understand the underlying resistance mechanisms that resulted from doxorubicin (DR), paclitaxel (PR), and tamoxifen (TAR). In total, 10,385 proteins were identified and quantified from three TMT 6-plex and one TMT 10-plex experiments. Bioinformatics analysis showed that Notch signaling, immune response, and protein re-localization processes were uniquely associated with DR, PR, and TAR resistance, respectively. In addition, proteomic signatures related to drug resistance were identified as potential targets of many FDA-approved drugs. Furthermore, we identified potential prognostic proteins with significant effects on overall survival. Representatively, PLXNB2 expression was associated with a highly significant increase in risk, and downregulation of ACOX3 was correlated with a worse overall survival rate. Consequently, our study provides new insights into the proteomic aspects of the distinct mechanisms underlying chemoresistance in breast cancer.
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Affiliation(s)
- Hyo Kyeong Cha
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul 03080, Korea; (H.K.C.); (H.K.)
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
| | - Seongmin Cheon
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
| | - Hyeyoon Kim
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul 03080, Korea; (H.K.C.); (H.K.)
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
| | - Kyung-Min Lee
- Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
| | - Han Suk Ryu
- Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: (H.S.R.); (D.H.)
| | - Dohyun Han
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul 03080, Korea; (H.K.C.); (H.K.)
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
- Correspondence: (H.S.R.); (D.H.)
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Ha D, Kim D, Kim I, Oh Y, Kong J, Han S, Kim S. Evolutionary rewiring of regulatory networks contributes to phenotypic differences between human and mouse orthologous genes. Nucleic Acids Res 2022; 50:1849-1863. [PMID: 35137181 PMCID: PMC8887464 DOI: 10.1093/nar/gkac050] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 01/14/2022] [Accepted: 01/25/2022] [Indexed: 11/14/2022] Open
Abstract
Mouse models have been engineered to reveal the biological mechanisms of human diseases based on an assumption. The assumption is that orthologous genes underlie conserved phenotypes across species. However, genetically modified mouse orthologs of human genes do not often recapitulate human disease phenotypes which might be due to the molecular evolution of phenotypic differences across species from the time of the last common ancestor. Here, we systematically investigated the evolutionary divergence of regulatory relationships between transcription factors (TFs) and target genes in functional modules, and found that the rewiring of gene regulatory networks (GRNs) contributes to the phenotypic discrepancies that occur between humans and mice. We confirmed that the rewired regulatory networks of orthologous genes contain a higher proportion of species-specific regulatory elements. Additionally, we verified that the divergence of target gene expression levels, which was triggered by network rewiring, could lead to phenotypic differences. Taken together, a careful consideration of evolutionary divergence in regulatory networks could be a novel strategy to understand the failure or success of mouse models to mimic human diseases. To help interpret mouse phenotypes in human disease studies, we provide quantitative comparisons of gene expression profiles on our website (http://sbi.postech.ac.kr/w/RN).
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Affiliation(s)
- Doyeon Ha
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | - Donghyo Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | | | - Youngchul Oh
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | - JungHo Kong
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | - Seong Kyu Han
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | - Sanguk Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
- Graduate School of Artificial Intelligence, Pohang University of Science and Technology, Pohang, Korea
- Institute of Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Korea
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Co-delivery of anticancer drugs via poly(ionic crosslinked chitosan-palladium) nanocapsules: Targeting more effective and sustainable cancer therapy. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Salvador D, Bastos V, Oliveira H. Hyperthermia Enhances Doxorubicin Therapeutic Efficacy against A375 and MNT-1 Melanoma Cells. Int J Mol Sci 2021; 23:ijms23010035. [PMID: 35008457 PMCID: PMC8744762 DOI: 10.3390/ijms23010035] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/17/2021] [Accepted: 12/18/2021] [Indexed: 12/28/2022] Open
Abstract
Melanoma is the deadliest form of skin cancer, and its incidence has alarmingly increased in the last few decades, creating a need for novel treatment approaches. Thus, we evaluated the combinatorial effect of doxorubicin (DOX) and hyperthermia on A375 and MNT-1 human melanoma cell lines. Cells were treated with DOX for 24, 48, and 72 h and their viabilities were assessed. The effect of DOX IC10 and IC20 (combined at 43 °C for 30, 60, and 120 min) on cell viability was further analyzed. Interference on cell cycle dynamics, reactive oxygen species (ROS) production, and apoptosis upon treatment (with 30 min at 43 °C and DOX at the IC20 for 48 h) were analyzed by flow cytometry. Combined treatment significantly decreased cell viability, but not in all tested conditions, suggesting that the effect depends on the drug concentration and heat treatment duration. Combined treatment also mediated a G2/M phase arrest in both cell lines, as well as increasing ROS levels. Additionally, it induced early apoptosis in MNT-1 cells, while in A375 cells this effect was similar to the one caused by hyperthermia alone. These findings demonstrate that hyperthermia enhances DOX effect through cell cycle arrest, oxidative stress, and apoptotic cell death.
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Pulukuri AJ, Burt AJ, Opp LK, McDowell CM, Davaritouchaee M, Nielsen AE, Mancini RJ. Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein. Pharmaceuticals (Basel) 2021; 14:ph14121292. [PMID: 34959691 PMCID: PMC8705394 DOI: 10.3390/ph14121292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/04/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could, therefore, benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We begin to address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod, Resiquimod, and Gardiquimod are substrates for P-gp. Interestingly, the least potent imidazoquinoline (Imiquimod) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. This suggests that enhancing efflux susceptibility could be an important consideration in the rational design of next generation immunotherapies that modulate activity of tumor-infiltrating immune cells.
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Affiliation(s)
- Anunay J. Pulukuri
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
| | - Anthony J. Burt
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA 92182, USA
| | - Larissa K. Opp
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
| | - Colin M. McDowell
- School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA;
| | - Maryam Davaritouchaee
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
- Department of Food Science, Cornell University, Ithaca, NY 14853, USA
- The Gene & Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164, USA
| | - Amy E. Nielsen
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
| | - Rock J. Mancini
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
- The Gene & Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164, USA
- Correspondence:
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Li J, Zhou W, Mao Q, Gao D, Xiong L, Hu X, Zheng Y, Xu X. HMGB1 Promotes Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cells by Inducing Autophagy via the AMPK/mTOR Signaling Pathway. Front Oncol 2021; 11:739145. [PMID: 34778055 PMCID: PMC8578906 DOI: 10.3389/fonc.2021.739145] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 10/12/2021] [Indexed: 12/26/2022] Open
Abstract
Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.
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Affiliation(s)
- Junhua Li
- Basic and Clinical Medical Research Center, Department of Gastroenterology, The First People's Hospital of Jingmen, Jingmen, China
| | - Wei Zhou
- Basic and Clinical Medical Research Center, Department of Gastroenterology, The First People's Hospital of Jingmen, Jingmen, China
| | - Qiang Mao
- Department of Statistics, The First People's Hospital of Jingmen, Jingmen, China
| | - Dandan Gao
- Department of Infectious Diseases, The First People's Hospital of Jingmen, Jingmen, China
| | - Lin Xiong
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xinyao Hu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongfa Zheng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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