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.
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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 62:122–135
Siegel R, Naishadham D, Jemal A (2013) Cancer statistics. CA Cancer J Clin 63(11):30
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 5:12670
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 12:1897–1905
Nandakumar DN, Nagaraj VA, Vathsala PG, Rangarajan P, Padmanaban G (2006) Curcumin-artemisinin combination therapy for malaria. Antimicrob Agents Chemother 50:1859–1860
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 39:283–299
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):651–654
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 9:234–240
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):2965–2971
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 269:199–225
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 36:2207–2215
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 223:181–190
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 35:3867–3873
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 97:115–119
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 34:2486–2497
Kumar A, Bora U (2013) Interactions of curcumin and its derivatives with nucleic acids and their implications. Mini-Rev Med Chem 13:256–264
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 6:30072
Underhill C, Toulmonde M, Bonnefoi H (2011) A review of PARP inhibitors: from bench to bedside. Ann Oncol 22:268–279
Memisoglu A, Samson L (2000) Base excision repair in yeast and mammals. Mutat Res 451:39–51
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 277:23028–23036
Almeida KH, Sobol RW (2007) A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification. DNA Repair (Amst) 6:695–711
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 26:1428–1438
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):1884–1888
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 13:2728–2737
Narod SA (2010) BRCA mutations in the management of breast cancer. Nat Rev Clin Oncol 7:702–707
Evans T, Matulonis U (2017) PARP inhibitors in ovarian cancer: evidence, experience and clinical potential. Ther Adv Med Oncol 9:253–267
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) 45:44–55
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 66:75–84
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 34:277–286
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 274:168–179
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 22:1205–1224
Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3:430
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 39:348–356
Martín-Cordero C, López-Lázaro M, Gálvez M, Ayuso MJ (2003) Curcumin as a DNA topoisomerase II poison. J Enzyme Inhibition Med Chem 18:505–509
Nitiss JL (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9:338
Prasad R, Horton JK, Dai DP, Wilson SH (2019) Repair pathway for PARP-1 DNA-protein crosslinks. DNA Repair 73:71–77
Wielgos M, Yang ES (2013) Discussion of PARP inhibitors in cancer therapy. Pharm Pat Anal 2:755–766
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):21–35
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 7:12876
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 103:18308–18313
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.
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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.
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Molla, S., Hembram, K.C., Chatterjee, S. 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. 26, 2091–2103 (2020). https://doi.org/10.1007/s12253-019-00768-0
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DOI: https://doi.org/10.1007/s12253-019-00768-0