PARP inhibitor Olaparib Enhances the Apoptotic Potentiality of Curcumin by Increasing the DNA Damage in Oral Cancer Cells through Inhibition of BER Cascade
- 59 Downloads
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.
KeywordsOral cancer Olaparib Curcumin PARP inhibitor PARylation
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.
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.
- 2.Siegel R, Naishadham D, Jemal A (2013) Cancer statistics. CA Cancer J Clin 63(11):30Google Scholar
- 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
- 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
- 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