A molecular basis for the synergy between 17-allylamino-17-demethoxy geldanamycin with Capecitabine and Irinotecan in human colorectal cancer cells through VEFG and MMP-9 gene expression

Zeynali M, S and Kheradmand, F and Mohammadian, M and Fathi Azarbaijani, A and Esnaashari, O and Yousef, R and Malekinejad, H (2018) A molecular basis for the synergy between 17-allylamino-17-demethoxy geldanamycin with Capecitabine and Irinotecan in human colorectal cancer cells through VEFG and MMP-9 gene expression. GENE. pp. 1-34.

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Abstract

Anti-proliferative, anti-metastatic and anti-angiogenic effects of 17-allylamino-17-demethoxy geldanamycin (17-AAG) were studied alone and in combination with Capecitabine (Cap) and/or Irinotecan (IR) on HT-29 human colorectal carcinoma cells. Expression of MMP-9 (matrix metalloproteinase-9) and VEGF (vascular endothelial growth factor) mRNA was analyzed by real-time PCR method. The study was further followed by wound scratch assay for migration assessment. Nitric oxide content, MDA generation and total anti-oxidant capacity were also assessed. Results showed significant differences between mono- and double therapy (p ˂ 0.05). Combination of 17-AAG with IR or Cap resulted in synergistic effect (Combination Index <1). Among double combination groups only Cap/17-AAG showed significant differences in MMP-9 and VEGF genes expression and wound healing assay. Moreover, a significant decrease of wound area in our triple combination group was obtained, indicating the antagonistic effect. IR/17-AAG and IR/Cap double combination groups resulted in down-regulation of MMP-9 and VEGF mRNA expression, respectively. Significant generation of MDA and decrease in TAC values have been observed in all our tested groups, however, the IR/17-AAG combination was the only group that could elevate NO concentration, significantly. Our findings demonstrated potent anti-angiogenesis and anti-metastatic effects for 17-AAG when it is provided in double combination especially with Cap, suggesting a new protocol in colorectal cancer combination therapy. These findings may indicate that down-regulation of VEGF and MMP-9 genes is directly related to angiogenesis and metastasis.

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