Abstract 5024: Role of protein kinase C ζ and ι inhibitors on ovarian cancer cell lines in combination with cisplatin

Abstract

Abstract Ovarian cancer causes more death than any other cancers of the female reproductive system. Current treatment strategies are surgical removal of cancerous parts and chemotherapy with platinum drugs (e.g. cisplatin, carboplatin) or taxols. However, recurrence of cancer with drug resistance is frequent. Previously two inhibitors; ICA-1S (5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide and ζ-stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid) specific for two atypical protein kinases, PKC-ι and PKC-ζ respectively have been reported. These inhibitors have an anticancer effect in different cancers, including clear-cell ovarian cancer. Our aim was to find if cisplatin has any synergistic effect with ICA-1S and ζ-stat on ovarian cancer cell proliferation, migration, and apoptosis. Ovarian cancer cell line ES-2, which has mutation in p53 gene was used in this study. After 72 hours of treatment with ICA-1S (10 µM) and ζ-stat (10 µM), proliferation of ES-2 cell line was inhibited by 42.5% and 23.5% respectively compared to control. When combined with cisplatin (0.5 µM), the inhibition of cell proliferation increased to 67% for ζ-stat and 65.8% for ICA-1S (N=3 trials) which is synergistic. Wound healing assay with ES-2 cells showed that ICA-1S and cisplatin inhibited the migration of ES-2 cells separately as well as in combination. SDS-PAGE and subsequent western blotting showed that ICA-1S monotherapy and combination with cisplatin reduced the expression mutant p53, PI3K, AKT, Bcl2, and phopho-BAD. IP with PKC ζ beads showed the association of PKC ζ with PKC-ι and p53 in ES-2 cell line. As mutation in p53 is quite frequent in ovarian cancer with gain of function, ICA-1S may have an advantageous role in inhibiting mutated p53 regulated pathway. Inhibition of ES-2 cell line with ICA-1S and ζ-stat also suggested that PKC-ι and PKC ζ play important roles in ovarian cancer and may augment traditional chemotherapy. Further study on the pathway affected by aPKC inhibitors combined with cisplatin would be investigated through WST, western blotting and immunoprecipitation assay. Citation Format: Mahfuza Marzan, Nuzhat Nowshin Oishee, Khandker Mohammad Khalid, Mildred Acevedo-Duncan. Role of protein kinase C ζ and ι inhibitors on ovarian cancer cell lines in combination with cisplatin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5024.