Nanoformulations of chemotherapeutic drugs are increasingly being studied for their potential to improve efficacy and safety. However, limited studies have been done on sequential dosing of nanochemotherapeutics and signal transduction inhibitors. In this study, pre-treatment and post-treatment dosing of PI-3 kinase inhibitor PI828 was used with cisplatin nanoparticles in murine breast cancer model. In vitro cell proliferation assay showed an enhanced cytotoxic capacity of cisplatin nanoparticle when used in combination with PI828. Moreover, post-treatment with the signal transduction inhibitors was found to be significantly more effective than pre-treatment. Western blot analysis showed a time dependent upregulation of phospho- AKT expression after administration of cisplatin nanoparticles, which was efficiently suppressed by PI828 in the post-treatment schedule. The upregulation of piAKT dependent signalling was mediated by both an EGFR dependent downstream activation of PI3 kinase pathway and an increased nuclear transcription of Akt gene. Post treatment with EGFR inhibitor (Erlotinib) showed similar enhancement in cytotoxicity of cisplatin nanoparticle.

In a 4T1 syngenic murine cancer in-vivo model, post-treatment with PI828 and Erlotinib following cisplatin nanoparticles treatment significantly suppressed tumor growth as compared to the pre-treatment or nanoparticles alone. These results indicate that sequence of administration of signal transduction inhibitors can impact the outcome of treatment with cisplatin nanotherapeutics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C187.