Abstract POSTER-THER-1428: Effects of atypical PKC inhibitors on ovarian cancer proliferation and RNA levels

Abstract

Abstract Ovarian cancers are highly lethal tumors which account for approximately four percent of all women’s cancers and are the fifth leading cause of cancer-related death among women. At diagnosis the majority of patients have metastatic disease and the long-term survival remains low. Certain ovarian cancers are highly lethal tumors due to the emergence of therapy-resistant ovarian cancer cells. Protein kinase C-iota (PKC-ι) has been shown to aid in the ability of cancer cells to resist drug-induced apoptosis. Recently, it has been reported that PKC-ι which is located in chromosome 3 at 3q26.2 is the most common genomic amplicon as identified by comparative genomic hybridization [Proc Natl Acad Sci U S A 102:12519–12524(2005)]. Additionally, an increase in PKC-ι DNA copy number was associated with decreased progression-free survival of ovarian cancer patients. Moreover, only PKC-ι gene amplification is highly correlated with protein overexpression, tumor size, lymph node metastasis and clinical stage out of four genes studied on the 3q26 amplification [Genes Chromosomes Cancer 47:127-136(2008)]. The focus of this research was to determine the in-vitro efficacy of the pan-atypical PKC inhibitor, 2-acetyl-1,3-cyclopentanedione (ACPD; Diabetes. 2014 Apr 4) and the novel PKC-iota inhibitor, ICA-1, (1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy) methyl]cyclopentyl]-,[1R-(1α, 2β, 3 β, 4 α) [The Inter. J. Biochem. & Cell Biol. 43:784-794(2011)] on HEY ovarian cancer cell proliferation and RNA concentration. In contrast to ACPD which inhibits both PKC-ι and PKC-zeta (PKC-ζ), ICA-1 specifically inhibits the activity of PKC-ι but not (PKC-ζ). The effects of ACPD and ICA-1on HEY proliferation was quantified by Trypan blue exclusion assay. RNA was isolated from treated and untreated cells using the Rneasy Mini Kit and protocol. Total RNA concentration was estimated using the NanoDrop1000 Spectrophotometer. Results showed that incubation of HEY ovarian cancer cells with ICA-1(1 μm) decreased proliferation by 41% compared to controls at 72 hours post-treatment. ICA-1(2 μM) reduced RNA levels by 17% at 72 hours post-treatment compared to controls. In contrast, ACPD (2 μM) inhibited proliferation by 82% compared to controls and RNA levels were reduced by 97% at 24 hours post-treatment. These results suggest the potential of ICA-1 and ACPD as chemotherapeutic agents. Citation Format: Minjel Shah, Christopher Apostolatos, Hercules Apostolatos, Mildred Acevedo-Duncan. Effects of atypical PKC inhibitors on ovarian cancer proliferation and RNA levels [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1428.