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.

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, Malondialdehyde 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.

• Authors: Shima Zeynali-Moghaddam, Mahshid Mohammadian, Fatemeh Kheradmand, Anahita Fathi-Azarbayjani, Yousef Rasmi, Omid Esna-Ashari, Hassan Malekinejad
• Journal: Gene (Gene) Vol. 684 Pg. 30-38 (Feb 05 2019) ISSN: 1879-0038 [Electronic] Netherlands
• PMID: 30315927 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Benzoquinones
• Lactams, Macrocyclic
• Vascular Endothelial Growth Factor A
• Deoxycytidine
• Capecitabine
• Irinotecan
• Matrix Metalloproteinase 9
• Fluorouracil
• Camptothecin
• geldanamycin

Topics

• Antineoplastic Combined Chemotherapy Protocols (metabolism)
• Benzoquinones (metabolism, pharmacology)
• Camptothecin (analogs & derivatives, metabolism)
• Capecitabine (metabolism, pharmacology)
• Colonic Neoplasms (drug therapy)
• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• Deoxycytidine (analogs & derivatives, metabolism)
• Fluorouracil (analogs & derivatives, metabolism)
• Gene Expression (drug effects)
• Gene Expression Regulation, Neoplastic (genetics)
• HT29 Cells
• Humans
• Irinotecan (metabolism, pharmacology)
• Lactams, Macrocyclic (metabolism, pharmacology)
• Matrix Metalloproteinase 9 (drug effects, genetics)
• Neovascularization, Pathologic (metabolism)
• Vascular Endothelial Growth Factor A (drug effects, genetics)