A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) is the second most lethal disease, with high mortality due to its heterogeneity and chemo-resistance. Here, we have focused on the epidermal growth factor receptor (EGFR) as an effective therapeutic target in CRC and studied the effects of polyphenols known to modulate several key signalling mechanisms including EGFR signalling, associated with anti-proliferative and anti-metastatic properties. EXPERIMENTAL APPROACH: Using ligand- and structure-based cheminformatics, we developed three potent, selective alkylaminophenols, 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), 2-[(1,2,3,4-tetrahydroquinolin-1-yl)(4-methoxyphenyl)methyl]phenol (THMPP) and N-[2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl]indoline (HNPMI). These alkylaminophenols were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and apoptosis induction, caspase activation and transcriptional and translational regulation. The lead compound HNPMI was evaluated in mice bearing xenografts of CRC cells. KEY RESULTS: Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC50 in CRC cells and potential cytotoxic effects on other tumour cells. Modulation of EGFR pathway down-regulated protein levels of osteopontin, survivin and cathepsin S, leading to apoptosis. Cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered the mRNA for and protein levels of several apoptosis-related proteins including caspase 3, BCL-2 and p53. HNPMI down-regulated the proteins crucial to oncogenesis in CRC cells. Assays in mice bearing CRC xenografts showed that HNPMI reduced the relative tumour volume. CONCLUSIONS AND IMPLICATIONS: HNPMI is a promising EGFR inhibitor for clinical translation. HNPMI regulated apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in CRC cell lines, showing potential as a therapeutic agent in the treatment of CRC.

In vitro anti-glioblastoma activity of L-valine derived boroxazolidones.

In the present study, a series of L-valine derived boroxazolidones, previously synthesized and reported to have residual activity in a human epithelial cell line, have been evaluated in vitro for their anti-glioblastoma activity. A boroxazolidone derivative containing 2,4-difluorophenyl moieties (6) was found to have higher cytotoxicity than the standard drug, Temozolomide (TMZ). Compound 6 was found to exhibit dose-dependent growth inhibitory effects with an IC50 of 49 µM and 53 µM for LN229 and SNB19 cells, respectively. Additionally, 6 was assessed for its role in apoptosis, caspase 3/7 activation and oxidative stress in SNB19 and LN229 cells. SNB19 cells treated with 6 showed 45.3% apoptosis in the population, while TMZ had 24.7%. In LN229 cells, the percentage of apoptotic cells treated with compound 6 and TMZ were the same. Both 6 and TMZ induced apoptosis through the activation of caspase 3/7 in SNB19 and LN229 cells. Interestingly, 6 exhibited a higher effectivity in promoting reactive oxygen species production in LN229, while it was 6-fold less in SNB19. Boroxazolidone-treated GBM cell lines increased reactive oxygen species production, suggesting that such species may be interlinked with the observed programmed cell death. Additionally, the treatment of both GBM cell lines with 6 led to G2/M phase arrest. The magnitude of anti-GBM effect of 6 is significantly higher than the known chemotherapeutic agent TMZ. This work further demonstrates the anticancer properties of L-valine derived boroxazolidones, adding another potential derivative to the collection of promising chemotherapeutic agents for GBM treatment.