Protein Kinase A–Mediated Effects of Protein Kinase C Partial Agonist 5-(Hydroxymethyl)Isophthalate 1a3 in Colorectal Cancer Cells

Abstract

Colorectal cancer is the third most commonly occurring cancer in men and the second in women. The global burden of colorectal cancer is projected to increase to over 2 million new cases with over 1 million deaths within the next 10 years and there is a great need for new compounds with novel mechanisms of action. Our group has developed PKC modulating isophthalic acid derivatives that induce cytotoxicity towards human cervical and prostate cancer cell lines. In this study, we investigated the effects of 5-(hydroxymethyl)isophthalate 1a3 (HMI-1a3) on colorectal cancer cell lines (Caco2, Colo205 and HT29). HMI-1a3 inhibited cell proliferation, decreased cell viability and induced an apoptotic response in all studied cell lines. These effects, however, were independent of PKC. Using serine/threonine kinome profiling and pharmacological kinase inhibitors we identified activation of the cAMP/PKA pathway as a new mechanism-of-action for HMI-1a3-induced anti-cancer activity in colorectal cancer cell lines. Our current results strengthen the hypothesis for HMI-1a3 as a potential anti-cancer agent against various malignancies.

Expanding the Paradigm of Structure-Based Drug Design: Molecular Dynamics Simulations Support the Development of New Pyridine-Based Protein Kinase C-Targeted Agonists

“…All PRDs were less potent than HMI-1a3 against prostate cancer metabolic activity. The effect on cell viability did not correlate with binding to PKC, which is in line with our previous work showing that the anticancer activity of the HMIs is most often mediated through a non-PKC-dependent route. ,, Altogether, PRDs 5b and 8a show very similar biological characteristics to the previously established HMI-1a3 in the studies described here.…”