Abstract 2827: In vivo effects of ICA-1 on breast cancer and glioma xenografts

Abstract

Abstract High grade breast cancer and gliomas are highly lethal tumors for which novel therapies are necessary. PKC-iota (PKC-α), an atypical protein kinase C isoform confers resistance to drug-induced apoptosis in cancer cells (J. Biol. Chem. 272; 44: 27521-27524). This research focuses on the in-vivo effects of the novel PKC-α inhibitor [1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy) methyl] cyclopentyl]-[1R-(1α, 2α, 3 β, 4 α)] (ICA-1; The Inter. J. Biochem. & Cell Biol. 43:784-794) on breast cancer and glioma xenografts. ICA-1 targets a unique sequence (amino acid residues 469-475) in the catalytic domain of PKC-α. The breast cancer xenograft study evaluated 12 athymic nude mice while the glioma xenograft study was comprised of 6 female athymic nude mice. The breast cancer xenografts were divided into saline control (n= 4) and xenografts injected with ICA-1 (20mg/kg; 5 μM; every other day, n = 8). The six glioma nude mice were divided into two groups consisting of saline controls (n = 3) and xenografts injected with ICA-1(80 mg/kg; 20 μM; every other day) when the tumor reached 100 mm3 on day 5 post implantation (n = 3). MDA-MB-468 breast cancer cells were injected subcutaneously (2 x106 cells/ flank in 0.2 ml PBS) while the human glioblastoma cell line U-87 MG was also injected into different mice subcutaneously in the right flank (1x106 cells/flank in 0.1 ml PBS). Tumor volume was calculated using formula: length x width x width x ½. Results showed that ICA-1 prevented glioma tumor growth even after stopping dosing at day 9 and continuing to monitor tumor growth for an additional nine days. Glioma tumor volume in these ICA-1 treated mice decreased by 51% compared to controls. ICA-1 was also effective in decreasing breast cancer xenograft growth by 50%. The weight of either ICA-1 treated breast cancer or glioma xenograft mice did not decrease compared to controls. These results indicate that ICA-1 is effective in preventing the growth of breast cancer and glioma xenografts. Future studies will establish toxicity data and optimize the dose and frequency of ICA-1 treatment for potential anti-PKC-α therapy. 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 2827. doi:1538-7445.AM2012-2827