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Zhao C. Exploring cell death pathways in oral cancer: mechanisms, therapeutic strategies, and future perspectives. Discov Oncol 2025; 16:395. [PMID: 40133563 PMCID: PMC11936869 DOI: 10.1007/s12672-025-02022-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 03/03/2025] [Indexed: 03/27/2025] Open
Abstract
Oral squamous cell carcinoma (OSCC) represents a significant global health challenge, characterized by aggressive progression and poor therapeutic response despite advances in treatment modalities. This review provides a comprehensive analysis of diverse cell death mechanisms in OSCC, encompassing traditional pathways (apoptosis, autophagy, and necrosis), newly characterized mechanisms (ferroptosis, pyroptosis, and necroptosis), and emerging pathways (cuproptosis, anoikis, parthanatos, and entosis). By examining the molecular basis of these pathways, particularly the crucial roles of p53 signaling and miRNA regulation, we highlight how their dysregulation contributes to treatment resistance and tumor progression. The review synthesizes recent evidence demonstrating the complex interplay between these ten distinct cell death mechanisms and their impact on the tumor microenvironment and immune response. We evaluate innovative therapeutic approaches that target these pathways, including novel small molecules, combination strategies, and immunomodulatory treatments that exploit specific cell death mechanisms to enhance therapeutic efficacy. Special attention is given to emerging personalized medicine strategies that consider individual tumor characteristics and cell death pathway profiles. By integrating current challenges with future research directions, this review provides a framework for developing more effective treatments that can leverage multiple cell death pathways to overcome therapy resistance and improve outcomes for oral cancer patients.
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Affiliation(s)
- Chenyi Zhao
- The Second School of Clinical Medicine, Guangdong Medical University, Dongguan, No.1 Xincheng Blvd, Songshan Lake National High-tech Industrial Development Zone, 523808, Guangdong Province, China.
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Choi S, Shin M, Kim WY. Targeting the DNA damage response (DDR) of cancer cells with natural compounds derived from Panax ginseng and other plants. J Ginseng Res 2025; 49:1-11. [PMID: 39872282 PMCID: PMC11764321 DOI: 10.1016/j.jgr.2024.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 03/30/2024] [Accepted: 04/01/2024] [Indexed: 01/30/2025] Open
Abstract
DNA damage is a driver of cancer formation, leading to the impairment of repair mechanisms in cancer cells and rendering them susceptible to DNA-damaging therapeutic approaches. The concept of "synthetic lethality" in cancer clinics has emerged, particularly with the use of PARP inhibitors and the identification of DNA damage response (DDR) mutation biomarkers, emphasizing the significance of targeting DDR in cancer therapy. Novel approaches aimed at genome maintenance machinery are under development to further enhance the efficacy of cancer treatments. Natural compounds from traditional medicine, renowned for their anti-aging and anticarcinogenic properties, have garnered attention. Ginseng-derived compounds, in particular, exhibit anti-carcinogenic effects by suppressing reactive oxygen species (ROS) and protecting cells from DNA damage-induced carcinogenesis. However, the anticancer therapeutic effect of ginseng compounds has also been demonstrated by inducing DNA damage and blocking DDR. This review concentrates on the biphasic effects of ginseng compounds on DNA mutations-both inhibiting mutation accumulation and impairing DNA repair. Additionally, it explores other natural compounds targeting DDR directly, providing potential insights into enhancing cancer therapy efficacy.
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Affiliation(s)
- SeokGyeong Choi
- College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Minwook Shin
- College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Woo-Young Kim
- College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
- Muscle Physiome Research Center, Sookmyung Women's University, Seoul, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul, Republic of Korea
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Elkafoury EM, El-Hamamsy MH, El-Bastawissy EA, Afarinkia K, Aboukhatwa SM. Synergy trap for guardian angels of DNA: Unraveling the anticancer potential of phthalazinone-thiosemicarbazone hybrids through dual PARP-1 and TOPO-I inhibition. Bioorg Chem 2024; 153:107924. [PMID: 39488147 DOI: 10.1016/j.bioorg.2024.107924] [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: 08/01/2024] [Revised: 10/19/2024] [Accepted: 10/25/2024] [Indexed: 11/04/2024]
Abstract
Targeting DNA repair, like PARP-1 and TOPO-I, shows promise in cancer therapy. However, resistance to single agents requires complex and costly combination strategies with significant side effects. Thus, there's an urgent need for single agents with dual inhibition. Current dual inhibitors focusing on the C-4 position of the phthalazinone core for PARP inhibition often have high molecular weights. Clinical use of PARP inhibitors is limited by hematological and other toxicities from concurrent PARP-2 inhibition. They're mainly effective in gynecological cancers, despite high PARP-1 and TOPO-I expression in various cancers. Moreover, their efficacy is limited to BRCA1-expressing breast cancer. In this study, we synthesized 27 dual inhibitors for PARP-1 and TOPO-I with molecular weights below 500 g/mol through hybridizing a phthalazinone core with a thiosemicarbazone linker. Among these, 6c demonstrated exceptional broad spectrum and potency against the NCI 60 cancer cell lines, with GI50 values from 1.65 to 5.63 µM. Notably, 6c exposed the highest PARP-1 inhibition (IC50 = 32.2 ± 3.26 nM) and a selectivity over PARP-2 (IC50 = 2844 ± 111 nM). Furthermore, 6c's inhibition of TOPO-I (IC50 = 46.2 ± 3.3 nM) surpassed the control camptothecin by eleven-fold. Mechanistically, 6c disrupted the cell cycle at the S phase, induced apoptosis, and displayed a favorable safety profile against normal cells. Compound 6c induced PARP trapping and synthetic lethality and showed high efficacy on BRCA1-expressing cell lines. So, decreasing the likelihood of cancer cell resistance to chemotherapy. Drug-likeness predictions and molecular modeling were also performed.
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Affiliation(s)
- Eman M Elkafoury
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Mervat H El-Hamamsy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Eman A El-Bastawissy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Kamyar Afarinkia
- School of Biomedical Sciences, University of West London, London W5 5RF, UK
| | - Shaimaa M Aboukhatwa
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
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Jacob S, Kather FS, Morsy MA, Boddu SHS, Attimarad M, Shah J, Shinu P, Nair AB. Advances in Nanocarrier Systems for Overcoming Formulation Challenges of Curcumin: Current Insights. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:672. [PMID: 38668166 PMCID: PMC11054677 DOI: 10.3390/nano14080672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/03/2024] [Accepted: 04/10/2024] [Indexed: 04/29/2024]
Abstract
Curcumin, an organic phenolic molecule that is extracted from the rhizomes of Curcuma longa Linn, has undergone extensive evaluation for its diverse biological activities in both animals and humans. Despite its favorable characteristics, curcumin encounters various formulation challenges and stability issues that can be effectively addressed through the application of nanotechnology. Nano-based techniques specifically focused on enhancing solubility, bioavailability, and therapeutic efficacy while mitigating toxicity, have been explored for curcumin. This review systematically presents information on the improvement of curcumin's beneficial properties when incorporated, either individually or in conjunction with other drugs, into diverse nanosystems such as liposomes, nanoemulsions, polymeric micelles, dendrimers, polymeric nanoparticles, solid-lipid nanoparticles, and nanostructured lipid carriers. Additionally, the review examines ongoing clinical trials and recently granted patents, offering a thorough overview of the dynamic landscape in curcumin delivery. Researchers are currently exploring nanocarriers with crucial features such as surface modification, substantial loading capacity, biodegradability, compatibility, and autonomous targeting specificity and selectivity. Nevertheless, the utilization of nanocarriers for curcumin delivery is still in its initial phases, with regulatory approval pending and persistent safety concerns surrounding their use.
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Affiliation(s)
- Shery Jacob
- Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates;
| | - Fathima Sheik Kather
- Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates;
| | - Mohamed A. Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (M.A.M.); (M.A.); (A.B.N.)
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Sai H. S. Boddu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman P.O. Box 346, United Arab Emirates;
- Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Mahesh Attimarad
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (M.A.M.); (M.A.); (A.B.N.)
| | - Jigar Shah
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India;
| | - Pottathil Shinu
- Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Anroop B. Nair
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (M.A.M.); (M.A.); (A.B.N.)
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Zaman N, Kushwah AS, Badriprasad A, Chakraborty G. Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 389:257-301. [PMID: 39396849 PMCID: PMC11855062 DOI: 10.1016/bs.ircmb.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomes PARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. Overcoming PARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate the PARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism of PARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond to PARPi.
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Affiliation(s)
- Nabila Zaman
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Atar Singh Kushwah
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Anagha Badriprasad
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Goutam Chakraborty
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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He S, Wang A, Wang J, Tang Z, Wang X, Wang D, Chen J, Liu C, Zhao M, Chen H, Song L. Human papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity. J Cancer Res Clin Oncol 2024; 150:27. [PMID: 38263342 PMCID: PMC10805821 DOI: 10.1007/s00432-023-05511-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/08/2023] [Indexed: 01/25/2024]
Abstract
PURPOSE Cervical cancer is a common gynecological malignancy, pathologically associated with persistent infection of high-risk types of human papillomavirus (HPV). Previous studies revealed that HPV-positive cervical cancer displays genomic instability; however, the underlying mechanism is not fully understood. METHODS To investigate if DNA damage responses are aggravated in precancerous lesions of HPV-positive cervical epithelium, cervical tissues were biopsied and cryosectioned, and subjected to immunofluorescent staining. Cloned HA-tagged E6 and E7 genes of HPV16 subtype were transfected into HEK293T or C33A cells, and indirect immunofluorescent staining was applied to reveal the competency of double strand break (DSB) repair. To test the synthetic lethality of E7-indued HRD and PARP inhibitor (PARPi), we expressed E7 in C33A cells in the presence or absence of olaparib, and evaluated cell viability by colony formation. RESULTS In precancerous lesions, endogenous DNA lesions were elevated along with the severity of CIN grade. Expressing high-risk viral factor (E7) in HPV-negative cervical cells did not impair checkpoint activation upon genotoxic insults, but affected the potential of DSB repair, leading to homologous recombination deficiency (HRD). Based on this HPV-induced genomic instability, the viability of E7-expressing cells was reduced upon exposure to PARPi in comparison with control cells. CONCLUSION In aggregate, our findings demonstrate that HPV-E7 is a potential driver for genome instability and provides a new angle to understand its role in cancer development. The viral HRD could be employed to target HPV-positive cervical cancer via synthetic lethality.
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Affiliation(s)
- Siqi He
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Ao Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Jing Wang
- Department of Clinical Laboratory, Suining Central Hospital, Suining, 629000, People's Republic of China
| | - Zizhi Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Xiaojun Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Danqing Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Jie Chen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Cong Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Mingcai Zhao
- Department of Clinical Laboratory, Suining Central Hospital, Suining, 629000, People's Republic of China.
| | - Hui Chen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
| | - Liang Song
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children's Hospital, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
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Bagheri M, Zandieh MA, Daryab M, Samaei SS, Gholami S, Rahmanian P, Dezfulian S, Eary M, Rezaee A, Rajabi R, Khorrami R, Salimimoghadam S, Hu P, Rashidi M, Ardakan AK, Ertas YN, Hushmandi K. Nanostructures for site-specific delivery of oxaliplatin cancer therapy: Versatile nanoplatforms in synergistic cancer therapy. Transl Oncol 2024; 39:101838. [PMID: 38016356 DOI: 10.1016/j.tranon.2023.101838] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/24/2023] [Accepted: 11/17/2023] [Indexed: 11/30/2023] Open
Abstract
As a clinically approved treatment strategy, chemotherapy-mediated tumor suppression has been compromised, and in spite of introducing various kinds of anticancer drugs, cancer eradication with chemotherapy is still impossible. Chemotherapy drugs have been beneficial in improving the prognosis of cancer patients, but after resistance emerged, their potential disappeared. Oxaliplatin (OXA) efficacy in tumor suppression has been compromised by resistance. Due to the dysregulation of pathways and mechanisms in OXA resistance, it is suggested to develop novel strategies for overcoming drug resistance. The targeted delivery of OXA by nanostructures is described here. The targeted delivery of OXA in cancer can be mediated by polymeric, metal, lipid and carbon nanostructures. The advantageous of these nanocarriers is that they enhance the accumulation of OXA in tumor and promote its cytotoxicity. Moreover, (nano)platforms mediate the co-delivery of OXA with drugs and genes in synergistic cancer therapy, overcoming OXA resistance and improving insights in cancer patient treatment in the future. Moreover, smart nanostructures, including pH-, redox-, light-, and thermo-sensitive nanostructures, have been designed for OXA delivery and cancer therapy. The application of nanoparticle-mediated phototherapy can increase OXA's potential in cancer suppression. All of these subjects and their clinical implications are discussed in the current review.
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Affiliation(s)
- Mohsen Bagheri
- Radiology Resident, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mahshid Daryab
- Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyedeh Setareh Samaei
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sarah Gholami
- Young Researcher and Elite Club, Babol Branch, Islamic Azad University, Babol, Iran
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sadaf Dezfulian
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mahsa Eary
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Aryan Rezaee
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Peng Hu
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Alireza Khodaei Ardakan
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
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Das C, Dash SR, Sinha S, Paul S, Das B, Bhal S, Sethy C, Kundu CN. Talazoparib enhances the quinacrine-mediated apoptosis in patient-derived oral mucosa CSCs by inhibiting BER pathway through the modulation of GCN5 and P300. Med Oncol 2023; 40:351. [PMID: 37940725 DOI: 10.1007/s12032-023-02222-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 10/12/2023] [Indexed: 11/10/2023]
Abstract
The presence of cancer stem cells (CSCs) in the tumor microenvironment (TME) is majorly responsible for the development and recurrence of cancer. Earlier reports suggested that upon DNA damage, poly-(ADP-ribose) polymerase-1 (PARP-1) helps in chromatin modulation and DNA repair process, thereby promoting CSC survival. But whether a combination of DNA damaging agents along with PARP inhibitors can modulate chromatin assembly, inhibit DNA repair processes, and subsequently target CSCs is not known. Hence, we have investigated the effect of nontoxic bioactive compound quinacrine (QC) and a potent PARP inhibitor Talazoparib in patient-derived oral mucosa CSCs (OM-CSCs) and in vivo xenograft mice preclinical model systems. Data showed that QC + Talazoparib inhibited the PARP-1-mediated chromatin remodelers' recruitment and deregulated HAT activity of GCN5 (general control nonderepressible-5) and P300 at DNA damage site, thereby preventing the access of repair proteins to the damaged DNA. Additionally, this combination treatment inhibited topoisomerase activity, induced topological stress, and induced apoptosis in OM-CSCs. Similar results were observed in an in vivo xenograft mice model system. Collectively, the data suggested that QC + Talazoparib treatment inhibited BER pathway, induced genomic instability and triggered apoptosis in OM-CSCs through the deregulation of PARP-1-mediated chromatin remodelers (GCN5 and P300) activity. Schematic representation of QC + Talazoparib-induced apoptosis in oral mucosa CSCs. (1) Induction of DNA damage takes place after QC treatment (2) PARP1-mediated PARylation at the site of DNA damage, which recruits multiple chromatin remodelers (3) Acetylation at the histone tails relax the structure of chromatin and recruits the BER pathway proteins at the site of DNA damage. (4) BER pathway activated at the site of DNA damage. (5) CSCs survive after successful repair of DNA damage. (6) Treatment of QC-treated CSCs with PARP inhibitor Talazoparib (7) Inhibition of PARylation results in failure of chromatin remodelers to interact with PARP1. (8) Inhibition of acetylation status leads to chromatin compaction. (9) BER pathway proteins are not recruited at the site of DNA damage, resulting in inhibition of BER pathway and accumulation of unrepaired DNA damage, leading to apoptosis and cell death.
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Affiliation(s)
- Chinmay Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Somya Ranjan Dash
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Saptarshi Sinha
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Subarno Paul
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Biswajit Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Subhasmita Bhal
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Chinmayee Sethy
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
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9
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Budi HS, Farhood B. Tumor microenvironment remodeling in oral cancer: Application of plant derived-natural products and nanomaterials. ENVIRONMENTAL RESEARCH 2023; 233:116432. [PMID: 37331557 DOI: 10.1016/j.envres.2023.116432] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/08/2023] [Accepted: 06/15/2023] [Indexed: 06/20/2023]
Abstract
Oral cancers consist of squamous cell carcinoma (SCC) and other malignancies in the mouth with varying degrees of invasion and differentiation. For many years, different modalities such as surgery, radiation therapy, and classical chemotherapy drugs have been used to control the growth of oral tumors. Nowadays, studies have confirmed the remarkable effects of the tumor microenvironment (TME) on the development, invasion, and therapeutic resistance of tumors like oral cancers. Therefore, several studies have been conducted to modulate the TME in various types of tumors in favor of cancer suppression. Natural products are intriguing agents for targeting cancers and TME. Flavonoids, non-flavonoid herbal-derived molecules, and other natural products have shown promising effects on cancers and TME. These agents, such as curcumin, resveratrol, melatonin, quercetin and naringinin have demonstrated potency in suppressing oral cancers. In this paper, we will review and discuss about the potential efficacy of natural adjuvants on oral cancer cells. Furthermore, we will review the possible therapeutic effects of these agents on the TME and oral cancer cells. Moreover, the potential of nanoparticles-loaded natural products for targeting oral cancers and TME will be reviewed. The potentials, gaps, and future perspectives for targeting TME by nanoparticles-loaded natural products will also be discussed.
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Affiliation(s)
- Hendrik Setia Budi
- Department of Oral Biology, Dental Pharmacology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Ye T, Lin A, Qiu Z, Hu S, Zhou C, Liu Z, Cheng Q, Zhang J, Luo P. Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity. iScience 2023; 26:107045. [PMID: 37448561 PMCID: PMC10336167 DOI: 10.1016/j.isci.2023.107045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 03/17/2023] [Accepted: 06/01/2023] [Indexed: 07/15/2023] Open
Abstract
There is an urgent need for markers to predict the efficacy of different chemotherapy drugs. Herein, we examined whether microsatellite instability (MSI) status can predict tumor multidrug sensitivity and explored the underlying mechanisms. We downloaded data from several public databases. Drug sensitivity was compared between the high microsatellite instability (MSI-H) and microsatellite-stable/low microsatellite instability (MSS/MSI-L) groups. In addition, we performed pathway enrichment analysis and cellular chemosensitivity assays to explore the mechanisms by which MSI status may affect drug sensitivity and assessed the differences between drug-treated and control cell lines. We found that multiple MSI-H tumors were more sensitive to a variety of chemotherapy drugs than MSS/MSI-L tumors, and especially for CRC, chemosensitivity is enhanced through the downregulation of DDR pathways such as NHEJ. Additional DNA damage caused by chemotherapeutic drugs results in further downregulation of DDR pathways and enhances drug sensitivity, forming a cycle of increasing drug sensitivity.
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Affiliation(s)
- Taojun Ye
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengang Qiu
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shulu Hu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Chaozheng Zhou
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Zaoqu Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Quan Cheng
- Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
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11
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Mukherjee D, Krishnan A. Therapeutic potential of curcumin and its nanoformulations for treating oral cancer. World J Methodol 2023; 13:29-45. [PMID: 37456978 PMCID: PMC10348080 DOI: 10.5662/wjm.v13.i3.29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/14/2023] [Accepted: 04/14/2023] [Indexed: 06/14/2023] Open
Abstract
The global incidence of oral cancer has steadily increased in recent years and is associated with high morbidity and mortality. Oral cancer is the most common cancer in the head and neck region, and is predominantly of epithelial origin (i.e. squamous cell carcinoma). Oral cancer treatment modalities mainly include surgery with or without radiotherapy and chemotherapy. Though proven effective, chemotherapy has significant adverse effects with possibilities of tumor resistance to anticancer drugs and recurrence. Thus, there is an imperative need to identify suitable anticancer therapies that are highly precise with minimal side effects and to make oral cancer treatment effective and safer. Among the available adjuvant therapies is curcumin, a plant polyphenol isolated from the rhizome of the turmeric plant Curcuma longa. Curcumin has been demonstrated to have anti-infectious, antioxidant, anti-inflammatory, and anticarcinogenic properties. Curcumin has poor bioavailability, which has been overcome by its various analogues and nanoformulations, such as nanoparticles, liposome complexes, micelles, and phospholipid complexes. Studies have shown that the anticancer effects of curcumin are mediated by its action on multiple molecular targets, including activator protein 1, protein kinase B (Akt), nuclear factor κ-light-chain-enhancer of activated B cells, mitogen-activated protein kinase, epidermal growth factor receptor (EGFR) expression, and EGFR downstream signaling pathways. These targets play important roles in oral cancer pathogenesis, thereby making curcumin a promising adjuvant treatment modality. This review aims to summarize the different novel formulations of curcumin and their role in the treatment of oral cancer.
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Affiliation(s)
- Diptasree Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
- Department of Medicine, Apex Institute of Medical Science, Kolkata 700075, West Bengal, India
| | - Arunkumar Krishnan
- Department of Medicine Section of Gastroenterology and Hepatology, West Virginia University School of Medicine, Morgantown, WV 26505, United States
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12
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Sinha S, Chatterjee S, Paul S, Das B, Dash SR, Das C, Kundu CN. Olaparib enhances the Resveratrol-mediated apoptosis in breast cancer cells by inhibiting the homologous recombination repair pathway. Exp Cell Res 2022; 420:113338. [PMID: 36075449 DOI: 10.1016/j.yexcr.2022.113338] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/29/2022] [Accepted: 08/31/2022] [Indexed: 11/15/2022]
Abstract
Although sensitization of BRCA-mutated, homologous recombination (HR)-deficient breast cancer cells through PARP inhibitor is widely studied, not much is known about the treatment of BRCA-wild-type, HR-proficient breast cancer. Here, we aim to investigate whether a bioactive compound, Resveratrol (RES), can induce DNA double-strand breaks in HR-proficient breast cancer cells and Olaparib (OLA), a PARP inhibitor, can enhance the RES-mediated apoptosis by deregulating the HR repair pathway. The detailed mechanism of anti-cancer action of RES + OLA combination in breast cancer has been evaluated using in vitro, ex vivo, and in vivo preclinical model systems. OLA increased RES-mediated DNA damage, downregulated the HR pathway proteins, caused a late S/G2 cell cycle arrest, enhanced apoptosis and cell death in RES pre-treated breast cancer cells at much lower concentrations than their individual treatments. Direct measurement of HR pathway activity using a GFP plasmid-based assay demonstrated reduced HR efficiency in I-SceI endonuclease-transfected cells treated with OLA. Moreover, RES + OLA treatment also caused significant reduction in PARP1-mediated PARylation and efficiently trapped PARP1 at the DNA damage site. Upon RES treatment, PARylated PARP1 was found to interact with BRCA1, which then activated other HR pathway proteins. But after addition of OLA in RES pre-treated cells, PARP1 could not interact with BRCA1 due to inhibition of PARylation. This resulted in deregulation of HR pathway. To further confirm the role of BRCA1 in PARP1-mediated HR pathway activation, BRCA1 was knocked down that caused complete inhibition of HR pathway activity, and further enhanced apoptosis after RES + OLA treatment in BRCA1-silenced cells. In agreement with in vitro data, similar experimental results were obtained in ex vivo patient-derived breast cancer cells and in vivo xenograft mice. Thus, RES + OLA combination treatment enhanced breast cancer cell death by causing excessive DNA damage and also simultaneously inhibiting the HR pathway.
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Affiliation(s)
- Saptarshi Sinha
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Subhajit Chatterjee
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Subarno Paul
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Biswajit Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Somya Ranjan Dash
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Chinmay Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India.
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13
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Lei H, He A, Jiang Y, Ruan M, Han N. Targeting DNA damage response as a potential therapeutic strategy for head and neck squamous cell carcinoma. Front Oncol 2022; 12:1031944. [PMID: 36338767 PMCID: PMC9634729 DOI: 10.3389/fonc.2022.1031944] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/05/2022] [Indexed: 12/20/2023] Open
Abstract
Cells experience both endogenous and exogenous DNA damage daily. To maintain genome integrity and suppress tumorigenesis, individuals have evolutionarily acquired a series of repair functions, termed DNA damage response (DDR), to repair DNA damage and ensure the accurate transmission of genetic information. Defects in DNA damage repair pathways may lead to various diseases, including tumors. Accumulating evidence suggests that alterations in DDR-related genes, such as somatic or germline mutations, single nucleotide polymorphisms (SNPs), and promoter methylation, are closely related to the occurrence, development, and treatment of head and neck squamous cell carcinoma (HNSCC). Despite recent advances in surgery combined with radiotherapy, chemotherapy, or immunotherapy, there has been no substantial improvement in the survival rate of patients with HNSCC. Therefore, targeting DNA repair pathways may be a promising treatment for HNSCC. In this review, we summarized the sources of DNA damage and DNA damage repair pathways. Further, the role of DNA damage repair pathways in the development of HNSCC and the application of small molecule inhibitors targeting these pathways in the treatment of HNSCC were focused.
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Affiliation(s)
- Huimin Lei
- School of Stomatology, Weifang Medical University, Weifang, China
| | - Ading He
- School of Stomatology, Weifang Medical University, Weifang, China
| | - Yingying Jiang
- School of Stomatology, Weifang Medical University, Weifang, China
| | - Min Ruan
- School of Stomatology, Weifang Medical University, Weifang, China
- Department of Oral Maxillofacio-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China
| | - Nannan Han
- School of Stomatology, Weifang Medical University, Weifang, China
- Department of Oral Maxillofacio-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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14
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Paul S, Sinha S, Kundu CN. Targeting cancer stem cells in the tumor microenvironment: An emerging role of PARP inhibitors. Pharmacol Res 2022; 184:106425. [PMID: 36075511 DOI: 10.1016/j.phrs.2022.106425] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/19/2022]
Abstract
Cancer stem cells (CSCs) constitute a small population of cancer cells in the tumor microenvironment (TME), which are responsible for metastasis, angiogenesis, drug resistance, and cancer relapse. Understanding the key signatures and resistance mechanisms of CSCs may help in the development of novel chemotherapeutic strategies to specifically target CSCs in the TME. PARP inhibitors (PARPi) are known to enhance the chemosensitivity of cancer cells to other chemotherapeutic agents by inhibiting the DNA repair pathways and chromatin modulation. But their effects on CSCs are still unknown. Few studies have reported that PARPi can stall replication fork progression in CSCs. PARPi also have the potential to overcome chemoresistance in CSCs and anti-angiogenic potentiality as well. Previous reports have suggested that epigenetic drugs can synergistically ameliorate the anti-cancer activities of PARPi through epigenetic modulations. In this review, we have systematically discussed the effects of PARPi on different DNA repair pathways with respect to CSCs and also how CSCs can be targeted either as monotherapy or as a part of combination therapy. We have also talked about how PARPi can help in reversal of chemoresistance of CSCs and the role of PARPi in epigenetic modifications to hinder cancer progression. We have also elaborated on the aspects of research that need to be investigated for development of successful therapeutic interventions using PARPi to specifically target CSCs in the TME.
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Affiliation(s)
- Subarno Paul
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Saptarshi Sinha
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India.
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15
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Chatterjee S, Dhal AK, Paul S, Sinha S, Das B, Dash SR, Kundu CN. Combination of talazoparib and olaparib enhanced the curcumin-mediated apoptosis in oral cancer cells by PARP-1 trapping. J Cancer Res Clin Oncol 2022; 148:3521-3535. [PMID: 35962813 DOI: 10.1007/s00432-022-04269-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 08/04/2022] [Indexed: 10/15/2022]
Abstract
PURPOSE Inhibition of Poly (ADP-ribose) Polymerases (PARP) results in the blocking of DNA repair cascades that eventually leads to apoptosis and cancer cell death. PARP inhibitors (PARPi) exhibit their actions either by inhibiting PARP-induced PARylation and/or by trapping PARP at the DNA damage site. But, the mechanism of PARPi-mediated induction of cellular toxicity via PARP-trapping is largely unknown. METHODS The cellular toxicity of PARPi [Talazoparib (BMN) and/or Olaparib (Ola)] was investigated in oral cancer cells and the underlying mechanism was studied by using in vitro, in silico, and in vivo preclinical model systems. RESULTS The experimental data suggested that induction of DNA damage is imperative for the optimal effectiveness of PARPi. Curcumin (Cur) exhibited maximum DNA damaging capacity in comparison to Resveratrol and 5-Flurouracil. Combination of BMN + Ola induced cell death in Cur pre-treated cells at much lower concentrations than their individual treatments. BMN + Ola treatment deregulated the BER cascade, potentiated PARP-trapping, caused cell cycle arrest and apoptosis in Cur pre-treated cells in a much more effective manner than their individual treatments. In silico data indicated the involvement of different amino acid residues which might play important roles in enhancing the BMN + Ola-mediated PARP-trapping. Moreover, in vivo mice xenograft data also suggested the BMN + Ola-mediated enhancement of apoptotic potentiality of Cur. CONCLUSION Thus, induction of DNA damage was found to be essential for optimal functioning of PARPi and BMN + Ola combination treatment enhanced the apoptotic potentiality of Cur in cancer cells by enhancing the PARP-trapping activity via modulation of BER cascade.
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Affiliation(s)
- Subhajit Chatterjee
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to Be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Ajit Kumar Dhal
- Bioinformatics Lab, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to Be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Subarno Paul
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to Be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Saptarshi Sinha
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to Be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Biswajit Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to Be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Somya Ranjan Dash
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to Be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to Be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India.
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16
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Sethy C, Kundu CN. PARP inhibitor BMN-673 induced apoptosis by trapping PARP-1 and inhibiting base excision repair via modulation of pol-β in chromatin of breast cancer cells. Toxicol Appl Pharmacol 2022; 436:115860. [PMID: 34998856 DOI: 10.1016/j.taap.2021.115860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 01/05/2023]
Abstract
PARP inhibitors emerged as clinically effective anti-tumor agents in combination with DNA damaging agents but the toxicity of DNA damaging agents and their off-target effects caused serious problems in cancer therapy. They confer cytotoxicity in cancer cells both by catalytic inhibition and trapping of PARP-1 at the DNA damage site. There is a lack of direct evidence to quantitatively determine the trapped PARP-1 in cellular DNA. Here, we have precisely evaluated the mechanism of PARP trapping mediated anti-cancer action of Quinacrine (QC), BMN-673, and their combination (QC + BMN-673) in breast cancer cells. We introduced a strategy to measure the cellular PARP trapping potentiality of BMN-673 in QC pretreated cells using a fluorescence-based assay system. It was found that QC+ BMN-673 induced apoptosis by triggering DNA damage in breast cancer cells. Treatment with QC + BMN-673 stimulated the expression of PARP-1 in the chromatin compared to that of PARP-2 and PARP-3. QC + BMN-673 treatment also caused a dose-dependent and time-dependent accumulation of PARP-1 and inhibition of PARylation in the chromatin. Upregulation of BER components (pol-β and FEN-1), an unchanged HR and NHEJ pathway proteins, and reduction of luciferase activity of the cells transfected with R-p21-P (LP-BER) were noted in combined drug-treated cells. Interestingly, silencing of pol-β resulted in unchanged PARP-1 trapping and PAR activity in the chromatin with increasing time after QC + BMN-673 treatment without altering APC and FEN-1 expression. Thus, our data suggested that the QC + BMN-673 augmented breast cancer cell death by pol-β mediated repair inhibition primarily through trapping of PARP-1 besides PARP-1 catalytic inhibition.
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Affiliation(s)
- Chinmayee Sethy
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology, Campus-11, Patia, Bhubaneswar, Odisha 751024, India.
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17
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Pradhan R, Chatterjee S, Hembram KC, Sethy C, Mandal M, Kundu CN. Nano formulated Resveratrol inhibits metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells by targeting tumor associated macrophages. J Nutr Biochem 2021; 92:108624. [PMID: 33705943 DOI: 10.1016/j.jnutbio.2021.108624] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 01/02/2021] [Accepted: 02/27/2021] [Indexed: 12/27/2022]
Abstract
Tumor associated macrophages in the tumor microenvironment secrete multiple cytokines, which regulate cancer cells growth and invasiveness. We systematically studied the role of cytokines in the induction of cancer stem like cells (CSCs) in oral cancer cells niche and evaluated the mechanism of Resveratrol nanoparticle (Res-Nano) mediated-reduction of CSCs properties in cells. A highly M1-like macrophages-enriched conditioned medium (CM) was generated by treating fixed doses of PMA and LPS in THP-1 cells alone as well as co-cultured of H-357 plus THP-1 cells. These M1-like macrophages increased the production of cytokines (e.g., TNF-α, IL-6, IL-1β, etc.). A CSCs populated environment was created after addition of cytokine-enriched-CM of co-culture of H-357 and THP-1 cells to cancer cells and cytokine enriched CM of THP-1 cells to patient derived primary oral cancer cells, respectively. After incubation with CM, enhancement of stemness, angiogenic and metastatic properties of both H-357 and primary oral cancer cells were noted. Res-NP decreased the cytokines level in CSCs-enriched cells and reduced the invasion, proliferation and growth of CSCs. Representative metastatic (CD133, ALDH1, CXCR4, etc.) and angiogenic markers (MMPs, iNOS, VEGF-A, etc.) were decreased after Res-NP treatment in CSCs enriched oral cancer cells niche. It also disrupted angiogenesis, depleted nitric oxide production in fertilized chick embryos and reduced the expression of metastatic and angiogenic markers in xenograft mice model system. Thus, this study concluded that CSCs-mediated stemness is a cytokine dependent phenomena and treatment of Res-NP inhibit this process in in vitro, in vivo and ex vivo systems.
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Affiliation(s)
- Rajalaxmi Pradhan
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar-751024, Odisha, India
| | - Subhajit Chatterjee
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar-751024, Odisha, India
| | - Krushna Chandra Hembram
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar-751024, Odisha, India
| | - Chinmayee Sethy
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar-751024, Odisha, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur-721302, West Bengal, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar-751024, Odisha, India.
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18
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Girisa S, Kumar A, Rana V, Parama D, Daimary UD, Warnakulasuriya S, Kumar AP, Kunnumakkara AB. From Simple Mouth Cavities to Complex Oral Mucosal Disorders-Curcuminoids as a Promising Therapeutic Approach. ACS Pharmacol Transl Sci 2021; 4:647-665. [PMID: 33860191 PMCID: PMC8033761 DOI: 10.1021/acsptsci.1c00017] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Indexed: 02/08/2023]
Abstract
Oral diseases are among the most common encountered health issues worldwide, which are usually associated with anomalies of the oral cavity, jaws, and salivary glands. Despite the availability of numerous treatment modalities for oral disorders, a limited clinical response has been observed because of the inefficacy of the drugs and countless adverse side effects. Therefore, the development of safe, efficacious, and wide-spectrum therapeutics is imperative in the battle against oral diseases. Curcumin, extracted from the golden spice turmeric, is a well-known natural polyphenol that has been extensively studied for its broad pleiotropic attributes and its ability to modulate multiple biological processes. It is well-documented to target pro-inflammatory mediators like NF-κB, ROS, COX-2, IL-1, IL-2, TGF-β, growth factors, apoptotic proteins, receptors, and various kinases. These properties make curcumin a promising nutraceutical in the treatment of many oral diseases like oral submucous fibrosis, oral mucositis, oral leukoplakia, oral erythroplakia, oral candidiasis, aphthous stomatitis, oral lichen planus, dental caries, periodontitis, and gingivitis. Numerous in vitro and in vivo studies have shown that curcumin alleviates the symptoms of most of the oral complications, including the inhibition of the progression of oral cancer. In this regard, many clinical trials have been completed, and many are ongoing to investigate the "curcumin effect" in oral maladies. Therefore, the current review delineates the mechanistic framework of curcumin's propensity in curbing oral diseases and present outcomes of the clinical trials of curcumin-based therapeutics that can provide a breakthrough in the clinical management of these diseases.
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Affiliation(s)
- Sosmitha Girisa
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Aviral Kumar
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Varsha Rana
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Dey Parama
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Uzini Devi Daimary
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Saman Warnakulasuriya
- Department
of Oral Medicine, King’s College
London and WHO Collaborating Centre for Oral Cancer and Precancer, London WC2R 2LS, United Kingdom
| | - Alan Prem Kumar
- Medical
Science Cluster, Cancer Translational Research Programme, Yong Loo
Lin School of Medicine, National University
of Singapore, Singapore 117600, Singapore
- Cancer
Science Institute of Singapore, National
University of Singapore, Singapore 117600, Singapore
- National
University Cancer Institute, National University
Health Systems, Singapore 117600, Singapore
| | - Ajaikumar B. Kunnumakkara
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
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19
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Lagunas-Rangel FA, Bermúdez-Cruz RM. Natural Compounds That Target DNA Repair Pathways and Their Therapeutic Potential to Counteract Cancer Cells. Front Oncol 2020; 10:598174. [PMID: 33330091 PMCID: PMC7710985 DOI: 10.3389/fonc.2020.598174] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/23/2020] [Indexed: 12/19/2022] Open
Abstract
Resistance to current cancer treatments is an important problem that arises through various mechanisms, but one that stands out involves an overexpression of several factors associated with DNA repair. To counteract this type of resistance, different drugs have been developed to affect one or more DNA repair pathways, therefore, to test different compounds of natural origin that have been shown to induce cell death in cancer cells is paramount. Since natural compounds target components of the DNA repair pathways, they have been shown to promote cancer cells to be resensitized to current treatments. For this and other reasons, natural compounds have aroused great curiosity and several research projects are being developed around the world to establish combined treatments between them and radio or chemotherapy. In this work, we summarize the effects of different natural compounds on the DNA repair mechanisms of cancer cells and emphasize their possible application to re-sensitize these cells.
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Affiliation(s)
- Francisco Alejandro Lagunas-Rangel
- Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City, Mexico
| | - Rosa María Bermúdez-Cruz
- Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City, Mexico
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Xiong Y, Guo Y, Liu Y, Wang H, Gong W, Liu Y, Wang X, Gao Y, Yu F, Su D, Wang F, Zhu Y, Zhao Y, Wu Y, Qin Z, Sun X, Ren B, Jiang B, Jin W, Shen Z, Tang Z, Song X, Wang L, Liu X, Zhou C, Jiang B. Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor. Neoplasia 2020; 22:431-440. [PMID: 32652442 PMCID: PMC7350150 DOI: 10.1016/j.neo.2020.06.009] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 02/01/2023] Open
Abstract
Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].
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Affiliation(s)
- Yao Xiong
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Yin Guo
- Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Ye Liu
- Department of Biochemistry, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Hexiang Wang
- Department of Chemistry, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Wenfeng Gong
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Yong Liu
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Xing Wang
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Yajuan Gao
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Fenglong Yu
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Dan Su
- Department of DMPK, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Fan Wang
- Department of DMPK, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Yutong Zhu
- Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Yuan Zhao
- Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Yiyuan Wu
- Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Zhen Qin
- Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Xuebing Sun
- Department of Biochemistry, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Bo Ren
- Department of Chemistry, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Bin Jiang
- Department of Discovery Biomarkers, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Wei Jin
- Department of Discovery Biomarkers, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Zhirong Shen
- Department of Discovery Biomarkers, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Zhiyu Tang
- Department of Clinic Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Xiaomin Song
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Lai Wang
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Xuesong Liu
- Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Changyou Zhou
- Department of Chemistry, BeiGene (Beijing) Co., Ltd., Beijing, PR China
| | - Beibei Jiang
- Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China.
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