A novel quinoline, MT477: suppresses cell signaling through Ras molecular pathway, inhibits PKC activity, and demonstrates in vivo anti-tumor activity against human carcinoma cell lines

Abstract

MT477 is a novel thiopyrano[2,3-c]quinoline that has been identified using molecular topology screening as a potential anticancer drug with a high activity against protein kinase C (PKC) isoforms. The objective of the present study was to determine the mechanism of action of MT477 and its activity against human cancer cell lines. MT477 interfered with PKC activity as well as phosphorylation of Ras and ERK1/2 in H226 human lung carcinoma cells. It also induced poly-caspase-dependent apoptosis. MT477 had a dose-dependent (0.006 to 0.2 mM) inhibitory effect on cellular proliferation of H226, MCF-7, U87, LNCaP, A431 and A549 cancer cell lines as determined by in vitro proliferation assays. Two murine xenograft models of human A431 and H226 lung carcinoma were used to evaluate tumor response to intraperitoneal administration of MT477 (33 microg/kg, 100 microg/kg, and 1 mg/kg). Tumor growth was inhibited by 24.5% in A431 and 43.67% in H226 xenografts following MT477 treatment, compared to vehicle controls (p < 0.05). In conclusion, our empirical findings are consistent with molecular modeling of MT477's activity against PKC. We also found, however, that its mechanism of action occurs through suppressing Ras signaling, indicating that its effects on apoptosis and tumor growth in vivo may be mediated by Ras as well as PKC. We propose, therefore, that MT477 warrants further development as an anticancer drug.

Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

“…Together, these observations reinforce the notion that PKC-dependent Ser181-phosphorylation of oncogenic KRAS is required for tumorigenesis. This effect may account for the previously reported inhibition of different KRAS-driven tumor xenografts by PKC pharmacologic inhibition (30,33,34). Interestingly, it has also been shown that PKCd knockdown prevents apoptosis and promotes tumorigenesis in cells addicted to aberrant KRAS signaling (35)(36)(37).…”

A Graph-Theoretical Approach to Calculate Vibrational Energies of Atomic and Subatomic Systems

“…Furthermore, our research group has cover a long way in the topological design of new drugs [28][29][30].…”

Synthesis of 7-chloroquinolinyl-4-

“…Other evidence has demonstrated that these kinds of structures, like the well known quinoline analog MT477, suppress cell signaling through Ras molecular pathway, inhibiting PKC activity. The effect of this compound is dose-dependent on H226, MCF-7, U87, LNCaP, A431 and A549 cancer cell lines [17]. Two murine xenograft models of human A431 and H226 lung carcinoma were used also to evaluate tumor response to intraperitoneal administration of MT477.…”