Advertisement

PARP inhibitor Olaparib Enhances the Apoptotic Potentiality of Curcumin by Increasing the DNA Damage in Oral Cancer Cells through Inhibition of BER Cascade

  • Sefinew Molla
  • Krushna Chandra Hembram
  • Subhajit Chatterjee
  • Deepika Nayak
  • Chinmayee Sethy
  • Rajalaxmi Pradhan
  • Chanakya Nath KunduEmail author
Original Article
  • 59 Downloads

Abstract

Although Olaparib (Ola, a PARP-inhibitor), in combination with other chemotherapeutic agents, was clinically approved to treat prostate cancer, but cytotoxicity, off-target effects of DNA damaging agents limit its applications in clinic. To improve the anti-cancer activity and to study the detailed mechanism of anti-cancer action, here we have used bioactive compound curcumin (Cur) in combination with Ola. Incubation of Ola in Cur pre-treated cells synergistically increased the death of oral cancer cells at much lower concentrations than individual optimum dose and inhibited the topoisomerase activity. Short exposure of Cur caused DNA damage in cells, but more increased DNA damage was noticed when Ola has incubated in Cur pre-treated cells. This combination did not alter the major components of homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways but significantly altered both short patch (SP) and long patch (LP) base excision repair (BER) components in cancer cells. Significant reduction in relative luciferase activity, expression of BER components and PARylation after Cur and Ola treatment confirmed this combination inhibit the BER activity in cells. Reduction of PARylation, decreased expression of BER components, decreased tumor volume and induction of apoptosis were also noticed in Cur + Ola treated Xenograft mice model. The combination treatment of Cur and Ola also helped in recovering the body weight of tumor-bearing mice. Thus, Cur + Ola combination increased the oral cancer cells death by not only causing the DNA damage but also blocking the induction of BER activity.

Keywords

Oral cancer Olaparib Curcumin PARP inhibitor PARylation 

Notes

Acknowledgments

We sincerely thank Department of Biotechnology, Govt. of India for providing research grant to CNK (ref# BT/PR22785/MED/30/1812/2016) and Govt. of Ethiopia, Ministry of Education for providing fellowship to SM.

Authors’ Contribution

Sefinew Molla carried out most of the experiments. Subhajit Chatterjee, Krushna Chandra Hembram, Deepika Nayak, Chinmayee Sethy and Rajalaxmi Pradhan help to analyze the data and writing the draft of the MS. Chanakya Nath Kundu conceived the idea design experiments and wrote final MS.

Compliance with Ethical Standards

Conflict of Interest

Authors declare that there are no conflicts of interest.

Supplementary material

12253_2019_768_MOESM1_ESM.docx (1.1 mb)
ESM 1 (DOCX 1110 kb)

References

  1. 1.
    Naik PP, Das DN, Panda PK, Mukhopadhyay S, Sinha N, Praharaj PP, Agarwal R, Bhutia SK (2016) Implications of cancer stem cells in developing therapeutic resistance in oral cancer. Oral Oncol 62:122–135CrossRefGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics. CA Cancer J Clin 63(11):30Google Scholar
  3. 3.
    Dufour R, Daumar P, Mounetou E (2015) BCRP and P-gp relay overexpression in triple negative basal-like breast cancer cell line: a prospective role in resistance to Olaparib. Sci Rep 5:12670CrossRefGoogle Scholar
  4. 4.
    Gelbard A, Garnett CT, Abrams SI, Patel V, Gutkind JS, Palena C, Tsang KY, Schlom J, Hodge JW (2006) Combination chemotherapy and radiation of human squamous cell carcinoma of the head and neck augments CTL-mediated lysis. Clin Cancer Res 12:1897–1905CrossRefGoogle Scholar
  5. 5.
    Nandakumar DN, Nagaraj VA, Vathsala PG, Rangarajan P, Padmanaban G (2006) Curcumin-artemisinin combination therapy for malaria. Antimicrob Agents Chemother 50:1859–1860CrossRefGoogle Scholar
  6. 6.
    Gupta SC, Patchva S, Koh W, Aggarwal BB (2012) Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol 39:283–299CrossRefGoogle Scholar
  7. 7.
    Satoskar RR, Shah SJ, Shenoy SG (1986) Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol 24(12):651–654PubMedGoogle Scholar
  8. 8.
    Shao ZM, Shen ZZ, Liu CH, Sartippour MR, Go VL, Heber D, Nguyen M (2002) Curcumin exerts multiple suppressive effects on human breast carcinoma cells. Int J Cancer 9:234–240CrossRefGoogle Scholar
  9. 9.
    Park CH, Hahm ER, Park S, Kim HK, Yang CH (2005) The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling. FEBS Lett 579(13):2965–2971CrossRefGoogle Scholar
  10. 10.
    Kunnumakkara AB, Anand P, Aggarwal BB (2008) Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett 269:199–225CrossRefGoogle Scholar
  11. 11.
    Shang HS, Chang CH, Chou YR, Yeh MY, Au MK, Lu HF, Chu YL, Chou HM, Chou HC, Shih YL, Chung JG (2016) Curcumin causes DNA damage and affects associated protein expression in HeLa human cervical cancer cells. Oncol Rep 36:2207–2215CrossRefGoogle Scholar
  12. 12.
    Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, Henry E, Dicato M, Diederich M (2005) Chemopreventive and therapeutic effects of curcumin. Cancer Lett 223:181–190CrossRefGoogle Scholar
  13. 13.
    Ting CY, Wang HE, Yu CC, Liu HC, Liu YC, Chiang IT (2015) Curcumin triggers DNA damage and inhibits expression of DNA repair proteins in human lung cancer cells. Anticancer Res 35:3867–3873PubMedGoogle Scholar
  14. 14.
    Zhao Q, Guan J, Qin Y, Ren P, Zhang Z, Lv J, Sun S, Zhang C, Mao W (2018) Curcumin sensitizes lymphoma cells to DNA damage agents through regulating Rad51-dependent homologous recombination. Biomed Pharmacother 97:115–119CrossRefGoogle Scholar
  15. 15.
    Ogiwara H, Ui A, Shiotani B, Zou L, Yasui A, Kohno T (2013) Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to a PARP inhibitor. Carcinogenesis 34:2486–2497CrossRefGoogle Scholar
  16. 16.
    Kumar A, Bora U (2013) Interactions of curcumin and its derivatives with nucleic acids and their implications. Mini-Rev Med Chem 13:256–264PubMedGoogle Scholar
  17. 17.
    Caiola E, Salles D, Frapolli R, Lupi M, Rotella G, Ronchi A, Garassino MC, Mattschas N, Colavecchio S, Broggini M, Wiesmüller L (2015) Base excision repair-mediated resistance to cisplatin in KRAS (G12C) mutant NSCLC cells. Oncotarget 6:30072CrossRefGoogle Scholar
  18. 18.
    Underhill C, Toulmonde M, Bonnefoi H (2011) A review of PARP inhibitors: from bench to bedside. Ann Oncol 22:268–279CrossRefGoogle Scholar
  19. 19.
    Memisoglu A, Samson L (2000) Base excision repair in yeast and mammals. Mutat Res 451:39–51CrossRefGoogle Scholar
  20. 20.
    Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, Fraulob V, Ménissier-de Murcia J, de Murcia G (2002) Poly (ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036CrossRefGoogle Scholar
  21. 21.
    Almeida KH, Sobol RW (2007) A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification. DNA Repair (Amst) 6:695–711CrossRefGoogle Scholar
  22. 22.
    Kundu CN, Balusu R, Jaiswal AS, Gairola CG, Narayan S (2007) Cigarette smoke condensate-induced level of adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells. Oncogene 26:1428–1438CrossRefGoogle Scholar
  23. 23.
    López-Lázaro M, Willmore E, Jobson A, Gilroy KL, Curtis H, Padget K, Austin CA (2007) Curcumin induces high levels of topoisomerase I- and II-DNA complexes in K562 leukemia cells. J Nat Prod 70(12):1884–1888CrossRefGoogle Scholar
  24. 24.
    Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC (2007) ABT-888, an orally active poly (ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13:2728–2737CrossRefGoogle Scholar
  25. 25.
    Narod SA (2010) BRCA mutations in the management of breast cancer. Nat Rev Clin Oncol 7:702–707CrossRefGoogle Scholar
  26. 26.
    Evans T, Matulonis U (2017) PARP inhibitors in ovarian cancer: evidence, experience and clinical potential. Ther Adv Med Oncol 9:253–267CrossRefGoogle Scholar
  27. 27.
    Siddharth S, Nayak D, Nayak A, Das S, Kundu CN (2016) ABT-888 and Quinacrine induced apoptosis in metastatic breast cancer stem cells by inhibiting base excision repair via adenomatous polyposis coli. DNA Repair (Amst) 45:44–55CrossRefGoogle Scholar
  28. 28.
    Mohapatra P, Satapathy SR, Siddharth S, Das D, Nayak A, Kundu CN (2015) Resveratrol and curcumin synergistically induce apoptosis in cigarette smoke condensate transformed breast epithelial cells through a p21Waf1/Cip1mediated inhibition of Hh-Gli signaling. Int J Biochem Cell Biol 66:75–84CrossRefGoogle Scholar
  29. 29.
    Preet R, Mohapatra P, Das D, Satapathy SR, Choudhuri T, Wyatt MD, Kundu CN (2013) Lycopene synergistically enhances Quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC. Carcinogenesis 34:277–286CrossRefGoogle Scholar
  30. 30.
    Mohapatra P, Preet R, Das D, Satapathy SR, Siddharth S, Choudhuri T, Wyatt MD, Kundu CN (2014) The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K-AKT-NFκB cascade. Toxicol Appl Pharmacol 274:168–179CrossRefGoogle Scholar
  31. 31.
    Das S, Tripathi N, Siddharth S, Nayak A, Nayak D, Sethy C, Bharatam PV, Kundu CN (2017) Etoposide and doxorubicin enhance the sensitivity of triple negative breast cancers through modulation of TRAIL-DR5 axis. Apoptosis 22:1205–1224CrossRefGoogle Scholar
  32. 32.
    Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3:430CrossRefGoogle Scholar
  33. 33.
    Wang L, Eastmond DA (2002) Catalytic inhibitors of topoisomerase II are DNA-damaging agents: induction of chromosomal damage by merbarone and ICRF-187. Environ Mol Mutagen 39:348–356CrossRefGoogle Scholar
  34. 34.
    Martín-Cordero C, López-Lázaro M, Gálvez M, Ayuso MJ (2003) Curcumin as a DNA topoisomerase II poison. J Enzyme Inhibition Med Chem 18:505–509CrossRefGoogle Scholar
  35. 35.
    Nitiss JL (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9:338CrossRefGoogle Scholar
  36. 36.
    Prasad R, Horton JK, Dai DP, Wilson SH (2019) Repair pathway for PARP-1 DNA-protein crosslinks. DNA Repair 73:71–77CrossRefGoogle Scholar
  37. 37.
    Wielgos M, Yang ES (2013) Discussion of PARP inhibitors in cancer therapy. Pharm Pat Anal 2:755–766CrossRefGoogle Scholar
  38. 38.
    Snyder RD, Arnone MR (2002) Putative identification of functional interactions between DNA intercalating agents and topoisomerase II using the V79 in vitro micronucleus assay. Mutat Res 503(1-2):21–35CrossRefGoogle Scholar
  39. 39.
    Prasad CB, Prasad SB, Yadav SS, Pandey LK, Singh S, Pradhan S, Narayan G (2017) Olaparib modulates DNA repair efficiency, sensitizes cervical cancer cells to cisplatin and exhibits anti-metastatic property. Sci Rep 7:12876CrossRefGoogle Scholar
  40. 40.
    Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC, Hurn PD (2006) Poly (ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci 103:18308–18313CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2019

Authors and Affiliations

  • Sefinew Molla
    • 1
  • Krushna Chandra Hembram
    • 1
  • Subhajit Chatterjee
    • 1
  • Deepika Nayak
    • 1
  • Chinmayee Sethy
    • 1
  • Rajalaxmi Pradhan
    • 1
  • Chanakya Nath Kundu
    • 1
    Email author
  1. 1.Cancer Biology Division, KIIT School of Biotechnology, Kalinga Institute of Industrial TechnologyDeemed to be UniversityBhubaneswarIndia

Personalised recommendations