Abstract
Cisplatin has been extensively used in therapeutics for its broad-spectrum anticancer activity and frequently used for thetreatment of solid tumors. However, it presents several side-effects and several cancers develop resistance. Combination therapy of cisplatin with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors has been effective in increasing its efficacy at lower doses. In this work, we have shown that the nitro-flavone derivative, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), can improve the sensitivity of cancer cells to cisplatin through inhibition of PARP1. The effect of 4NCO on cisplatin toxicity was studied through combination therapy in both exponential and density inhibited A375 melanoma cells. Combination index (CI) was determined from isobologram analysis. The mechanism of cell killing was assessed by lactate dehydrogenase (LDH) assay. Temporal nicotinamide adenine dinucleotide (NAD+) assay was done to show the inhibition of PARP1. We also performed in silico molecular modeling studies to know the binding mode of 4NCO to a modeled PARP1-DNA complex containing cisplatin-crosslinked adduct. The results from both in silico and in cellulo studies confirmed that PARP1 inhibition by 4NCO was most effective in sensitizing A375 melanoma cells to cisplatin. Isobologram analysis revealed that 4NCO reduced cell viability both in exponential and density inhibited A375 cells synergistically. The combination led to cell death through apoptosis. The synthetic nitro-flavone derivative 4NCO effectively inhibited the important nuclear DNA repair enzyme PARP1 and therefore, could complement the DNA-damaging anticancer drug cisplatin in A375 cells and thus, could act as a potential adjuvant to cisplatin in melanoma therapy.
Highlights
Cisplatin has been widely used as an anticancer agent in the treatment of different types of cancer that includes - brain tumors, neuroblastoma, mesothelioma, head and neck cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, testicular cancer, bladder cancer, esophageal cancer, cancer of bones, muscles, soft tissue, blood, etc
In this work, we have shown that the nitro-flavone derivative, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), can improve the sensitivity of cancer cells to cisplatin through inhibition of poly (ADP-ribose) polymerase 1 (PARP1)
We performed in silico molecular modeling studies to know the binding mode of 4NCO to a modeled PARP1-DNA complex containing cisplatin-crosslinked adduct
Summary
Cisplatin has been widely used as an anticancer agent in the treatment of different types of cancer that includes - brain tumors, neuroblastoma, mesothelioma, head and neck cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, testicular cancer, bladder cancer, esophageal cancer, cancer of bones, muscles, soft tissue, blood, etc. The repair enzymes are activated immediately on detection of the cisplatin-induced DNA lesions initiating repair activities [1] Drugs inhibiting these enzymes are often used as an adjuvant to sensitize cells to cisplatin at low doses. One such important repair enzyme is poly (ADP-ribose) polymerase 1 (PARP1) [4][5]. The NAD+ level in cells on cotreatment with 4NCO and cisplatin was estimated to see whether its effect on cisplatin-induced killing of cancer cells was mediated through inhibition of PARP1 activity. Cisplatin has been extensively used in therapeutics for its broad-spectrum anticancer activity and frequently used for the treatment of solid tumors It presents several side-effects and several cancers develop resistance. Combination therapy of cisplatin with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors has been effective in increasing its efficacy at lower doses
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
