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Talazoparib enhances the quinacrine-mediated apoptosis in patient-derived oral mucosa CSCs by inhibiting BER pathway through the modulation of GCN5 and P300

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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.

Graphical abstract

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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Data availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Abbreviations

CSCs:

Cancer stem cells

FBS:

Fetal bovine serum

FDA:

Food and Drug Administration

GCN5:

General control nonderepressible-5

HAT:

Histone acetyltransferase

OM-CSCs:

Oral mucosa cancer stem like cells

PARP1:

Poly-(ADP-ribose) polymerase 1

PBS:

Phosphate buffered saline

PDX:

Patient-derived xenograft

P-EMT:

Post-epithelial to mesenchymal transformed

QC:

Quinacrine

TME:

Tumor microenvironment

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  2. Markopoulos AK. Current aspects on oral squamous cell carcinoma. Open Dent J. 2012;6:126.

    PubMed  PubMed Central  Google Scholar 

  3. Bhal S, Kundu CN. Targeting crosstalk of signaling pathways in cancer stem cells: a promising approach for development of novel anti-cancer therapeutics. Med Oncol. 2023;40:82.

    PubMed  Google Scholar 

  4. Vinogradov S, Wei X. Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomedicine. 2012;7:597–615.

    PubMed  CAS  Google Scholar 

  5. Amjad MT, Chidharla A, Kasi A. Cancer chemotherapy. StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2023 [cited 2023 Apr 20]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK564367/.

  6. Guo C, Gasparian AV, Zhuang Z, Bosykh DA, Komar AA, Gudkov AV, et al. 9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways. Oncogene. 2009;28:1151–61.

    PubMed  CAS  Google Scholar 

  7. Gurova K. New hopes from old drugs: revisiting DNA-binding small. Future Oncol. 2010;5:1–28.

    Google Scholar 

  8. Das B, Kundu CN. Anti-cancer stem cells potentiality of an anti-malarial agent quinacrine: an old wine in a new bottle. Anti-Cancer Agents Med Chem. 2021;21:416–27.

    Google Scholar 

  9. Preet R, Mohapatra P, Mohanty S, Sahu SK, Choudhuri T, Wyatt MD, et al. Quinacrine has anticancer activity in breast cancer cells through inhibition of topoisomerase activity. Int J Cancer. 2012;130:1660–70.

    PubMed  CAS  Google Scholar 

  10. Preet R, Mohapatra P, Das D, Satapathy SR, Choudhuri T, Wyatt MD, et al. Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC. Carcinogenesis. 2013;34:277–86.

    PubMed  CAS  Google Scholar 

  11. Nayak A, Satapathy SR, Das D, Siddharth S, Tripathi N, Bharatam PV, et al. Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: role of GLI-1. Sci Rep. 2016;6:1–16.

    Google Scholar 

  12. Völker-Albert M, Bronkhorst A, Holdenrieder S, Imhof A. Histone modifications in stem cell development and their clinical implications. Stem Cell Rep. 2020;15:1196–205.

    Google Scholar 

  13. Ghasemi S, Xu S, Nabavi SM, Amirkhani MA, Sureda A, Tejada S, et al. Epigenetic targeting of cancer stem cells by polyphenols (cancer stem cells targeting). Phytother Res. 2021;35:3649–64.

    PubMed  CAS  Google Scholar 

  14. Sinha S, Molla S, Kundu CN. PARP1-modulated chromatin remodeling is a new target for cancer treatment. Med Oncol. 2021;38:1–16.

    Google Scholar 

  15. Zhang P, Torres K, Liu X, Liu C, Pollock RE. An overview of chromatin-regulating proteins in cells. Curr Protein Peptide Sci. 2016;17:401–10.

    CAS  Google Scholar 

  16. Trisciuoglio D, Di Martile M, Del Bufalo D. Emerging role of histone acetyltransferase in stem cells and cancer. Stem Cells Int. 2018;2018:8908751.

    PubMed  PubMed Central  Google Scholar 

  17. Guo P, Chen W, Li H, Li M, Li L. The histone acetylation modifications of breast cancer and their therapeutic implications. Pathol Oncol Res. 2018;24:807–13.

    PubMed  CAS  Google Scholar 

  18. Marmorstein R, Roth SY. Histone acetyltransferases: function, structure, and catalysis. Curr Opin Genet Dev. 2001;11:155–61.

    PubMed  CAS  Google Scholar 

  19. Xu Y-M, Du J-Y, Lau AT. Posttranslational modifications of human histone H3: an update. Proteomics. 2014;14:2047–60.

    PubMed  Google Scholar 

  20. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Kuo Y-M, Andrews AJ. Quantitating the specificity and selectivity of Gcn5-mediated acetylation of histone H3. PLoS ONE. 2013;8: e54896.

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Haque ME, Jakaria M, Akther M, Cho D-Y, Kim I-S, Choi D-K. The GCN5: its biological functions and therapeutic potentials. Clin Sci. 2021;135:231–57.

    Google Scholar 

  23. Iyer NG, Özdag H, Caldas C. p300/CBP and cancer. Oncogene. 2004;23:4225–31.

    PubMed  CAS  Google Scholar 

  24. Wang L, Chen K, Chen Z. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome. Nat Commun. 2021;12:1–9.

    Google Scholar 

  25. Qi W, Chen H, Lu C, Bu Q, Wang X, Han L. BRG1 promotes chromatin remodeling around DNA damage sites. Anim Cells Syst. 2018;22:360–7.

    CAS  Google Scholar 

  26. Wu T, Kamikawa YF, Donohoe ME. Brd4’s bromodomains mediate histone H3 acetylation and chromatin remodeling in pluripotent cells through P300 and Brg1. Cell Rep. 2018;25:1756–71.

    PubMed  CAS  Google Scholar 

  27. Rose M, Burgess JT, O’Byrne K, Richard DJ, Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol. 2020;8: 564601.

    PubMed  PubMed Central  Google Scholar 

  28. 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.

    PubMed  CAS  Google Scholar 

  29. Molla S, Chatterjee S, Sethy C, Sinha S, Kundu CN. Olaparib enhances curcumin-mediated apoptosis in oral cancer cells by inducing PARP trapping through modulation of BER and chromatin assembly. DNA Repair. 2021;105: 103157.

    PubMed  CAS  Google Scholar 

  30. Sinha S, Chatterjee S, Paul S, Das B, Dash SR, Das C, et al. Olaparib enhances the Resveratrol-mediated apoptosis in breast cancer cells by inhibiting the homologous recombination repair pathway. Exp Cell Res. 2022;420: 113338.

    PubMed  CAS  Google Scholar 

  31. Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency BMN 673, a highly potent PARP inhibitor. Clin Cancer Res. 2013;19:5003–15.

    PubMed  PubMed Central  CAS  Google Scholar 

  32. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA [Internet]. 2019 [cited 2023 Mar 9]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-gbrcam-her2-negative-locally-advanced-or-metastatic-breast-cancer.

  33. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27:5904–12.

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Sethy C, Goutam K, Nayak D, Pradhan R, Molla S, Chatterjee S, et al. Clinical significance of a pvrl 4 encoded gene Nectin-4 in metastasis and angiogenesis for tumor relapse. J Cancer Res Clin Oncol. 2020;146:245–59.

    PubMed  CAS  Google Scholar 

  35. Dash SR, Chatterjee S, Sinha S, Das B, Paul S, Pradhan R, et al. NIR irradiation enhances the apoptotic potentiality of quinacrine-gold hybrid nanoparticles by modulation of HSP-70 in oral cancer stem cells. Nanomed Nanotechnol Biol Med. 2022;40:102502.

    CAS  Google Scholar 

  36. Hembram KC, Dash SR, Das B, Sethy C, Chatterjee S, Bindhani BK, et al. Quinacrine based gold hybrid nanoparticles caused apoptosis through modulating replication fork in oral cancer stem cells. Mol Pharm. 2020;17:2463–72.

    PubMed  CAS  Google Scholar 

  37. Nayak D, Tripathi N, Kathuria D, Siddharth S, Nayak A, Bharatam PV, et al. Quinacrine and curcumin synergistically increased the breast cancer stem cells death by inhibiting ABCG2 and modulating DNA damage repair pathway. Int J Biochem Cell Biol. 2020;119: 105682.

    PubMed  CAS  Google Scholar 

  38. 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.

    PubMed  CAS  Google Scholar 

  39. Molla S, Hembram KC, Chatterjee S, Nayak D, Sethy C, Pradhan R, et al. PARP inhibitor olaparib enhances the apoptotic potentiality of curcumin by increasing the DNA damage in oral cancer cells through inhibition of BER cascade. Pathol Oncol Res. 2020;26:2091–103.

    PubMed  CAS  Google Scholar 

  40. Das D, Preet R, Mohapatra P, Satapathy SR, Siddharth S, Tamir T, et al. 5-fluorouracil mediated anti-cancer activity in colon cancer cells is through the induction of adenomatous polyposis coli: implication of the long-patch base excision repair pathway. DNA Repair. 2014;24:15–25.

    PubMed  PubMed Central  CAS  Google Scholar 

  41. 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.

    PubMed  CAS  Google Scholar 

  42. Karakaidos P, Karagiannis D, Rampias T. Resolving DNA damage: epigenetic regulation of DNA repair. Molecules. 2020;25:2496.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Audia JE, Campbell RM. Histone modifications and cancer. Cold Spring Harb Perspect Biol. 2016;8: a019521.

    PubMed  PubMed Central  Google Scholar 

  44. Ubhi T, Brown GW. Exploiting DNA replication stress for cancer treatmentexploiting replication stress. Can Res. 2019;79:1730–9.

    CAS  Google Scholar 

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Acknowledgements

The authors acknowledge Indian Council of Medical Research (ICMR), Government of India for providing research grant (F. No: 2016-0043/SCR/ADHOC-BMS) to CNK. The authors also thankful to Acharya Harihar Regional Cancer Centre (AHRCC), Cuttack, Odisha, India for providing patient sample for the experiments.

Funding

This work was supported by Indian Council of Medical Research (F. No: 2016-0043/SCR/ADHOC-BMS), Government of India.

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Authors and Affiliations

  1. Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India

    Chinmay Das, Somya Ranjan Dash, Saptarshi Sinha, Subarno Paul, Biswajit Das, Subhasmita Bhal, Chinmayee Sethy & Chanakya Nath Kundu

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Contributions

CD: Conceptualization, Methodology, Investigation, Validation, Visualization, Writing—original draft. SRD: Formal analysis, Validation, Visualization, Methodology, Writing—Review & Editing. SS: Formal analysis, Visualization, Methodology, Writing—Review & Editing. SP: Formal analysis, Validation, Resources, Methodology. BD: Validation, Visualization, Methodology. SB: Resources, Methodology. CS: Methodology. CNK: Conceptualization, Methodology, Investigation, Validation, Visualization, Project administration, Supervision, Funding acquisition, Writing—Review & Editing.

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Correspondence to Chanakya Nath Kundu.

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Conflict of interest

The authors declared that there are no conflicts of interest.

Ethical approval

All the patient tissue samples were used to carry out experiments by following the guidelines of the Declaration of Helsinki after getting the formal approval of the Institutional Ethics Committee (Ethical clearance approval letter No: 96-IEC-AHRCC) from Acharya Harihar Regional Cancer Centre, Cuttack, Odisha, India. Mice were used to carry out experiments by following the ARRIVE guidelines and the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), New Delhi, India after receiving the formal approval (Ethical clearance approval Regd. #KSBT/IAEC/2022/MEET-1/A1) of Institutional Animal Ethics Committee (IAEC), KIIT University.

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Das, C., Dash, S.R., Sinha, S. et al. 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 40, 351 (2023). https://doi.org/10.1007/s12032-023-02222-3

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