Abstract 2821: The PKC-iota inhibitor ICA-1 overcomes chemoresistance and induces cell death in glioblastoma multiforme

Abstract

Abstract Glioblastoma multiforme is a very aggressive brain cancer that is refractory to most chemotherapeutics. The standard of care for glioblastoma patients is the administration of temozolomide following surgery. However, temozolomide provides an approximately 20% enhanced survival rate. Therefore, it is imperative to develop other novel chemotherapeutics to better enhance the survival rate and induce tumor regression in patients. A potential candidate for a pre-clinical glioblastoma study is the novel chemotherapeutic, ICA-1. ICA-1 is a PKC-iota inhibitor which specifically inhibits PKC-iota and not its homologue, PKC-zeta. Results demonstrated that ICA-1 inhibited cell proliferation rates in a range of T98G glioblastoma concentrations in vitro. Also, results showed that low density T98G cultures which have a high proliferation status and high S-phase promotion concomitantly demonstrated resistance to ICA-1 treatment. However, high density T98G cultures which have a lower proliferation status and low S-phase promotion are concurrently chemosensitive toward ICA-1. At 48h post ICA-1 treatment, the majority of cells in the high density cultures were in G0/G1 with a rise of cells in this phase of the cell cycle shown by day 5 post-treatment. Conversely, between 48h and day 5, 30-44% of cells from the low density cultures were in S phase irrespective of ICA-1 therapy. Furthermore, by day 5 post-treatment, ICA-1 induced significant cell death in T98G cells only at higher ranges (i.e., 20-40 microM of ICA-1). Interestingly, 40 microM ICA-1 caused a significant cell death rate of 45% when 7,500 cells were seeded into a 24-well plate on Day 0 followed by ICA-1 exposure on the next day. Forty microM ICA-1 induced 15% cell death when 3,750 cells were seeded. There was a stepwise increase in the amount of ICA-1 required to induce cell death as the cell concentration increased (i.e., high density T98G cultures required elevated levels of ICA-1). Therefore, the data suggested that the G0/G1 phase glioblastoma cells (i.e., the higher cell concentrations) were more sensitive to 40 microM ICA-1 therapy. Whereas, the S phase glioblastoma cells were less sensitive to the ICA-1 therapy. Future animal models may show that the more aggressive the tumor becomes, the greater the potential for the effectiveness of ICA-1 (i.e., greater chemosensitivity). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2821. doi:1538-7445.AM2012-2821