Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines

Abstract

The use of heat shock protein 90 inhibitors like 17-allylamino-17-demethoxy-geldanamycin (17-AAG) has been recently introduced as an attractive anticancer therapy. It has been shown that 17-AAG may potentiate the inhibitory effects of some classical anticolorectal cancer (CRC) agents. In this study, two panels of colorectal carcinoma cell lines were used to evaluate the effects of 17-AAG in combination with capecitabine and oxaliplatin as double and triple combination therapies on the proliferation of CRC cell lines. HT-29 and all HCT-116 cell lines were seeded in culture media in the presence of different doses of the mentioned drugs in single, double, and triple combinations. Water-soluble tetrazolium-1 (WST-1) assay was used to investigate cell proliferation 24 h after treatments. Then, dose-response curves were plotted using WST-1outputs, and IC₅₀ values were determined. For double and triple combinations respectively 0.5 × IC₅₀ and 0.25 × IC₅₀ were used. Data was analyzed with the software CompuSyn. Drug interactions were analyzed using Chou-Talalay method to calculate the combination index (CI).The data revealed that 17-AAG shows a potent synergistic interaction (CI < 1) with oxaliplatin and capecitabine in double combinations (0.5 × IC₅₀) in both cell lines. In the case of triple combinations, the findings showed an antagonistic interaction (CI > 1) in HT-29 and a synergistic effect (CI < 1) in HCT-116 (0.25 × IC₅₀) cell lines. It was concluded that double combinations of 17-AAG with oxaliplatin or capecitabine might be effective against HCT-116 and HT-29 cell lines. However, in triple combinations, positive results were seen only against HCT-116. Further investigation is suggested to confirm the effectiveness of these combinations in clinical trials.

Keywords: 17-AAG; Capecitabine; Colorectal cancer; HCT-116; HT-29; Oxaliplatin.

Fig. 1

Cytotoxic effects of (A), 17-allylamino-17-demethoxygeldanamycin; (B), capecitabine, and (C), oxaliplatin in single drug treatments with different doses on HT-29 and HCT-116 cell proliferation. Sensitivity to three antineoplastic agents was determined by cell viability test, water-soluble tetrazolium-1 on HT-29 and HCT-116 cells. Each plot represents the average of at least 3 experiments. Data presented as mean ± standard deviation.

Fig. 2

Water-soluble tetrazolium-1 (WST-1, cell viability assay) results of capecitabine, oxaliplatin, and 17-AAG in double combinations (2 × IC₅₀, 1 × IC₅₀, 0.5 × IC₅₀, and 0.25 × IC₅₀) and triple combinations (1 × IC₅₀, 0.5 × IC₅₀, and 0.25 × IC₅₀) at different concentrations of each drug on (A), HCT-116 and (B), HT-29 cells. Data are presented as mean ± standard deviation. (17-AAG), 17-allylamino-17-demethoxygeldanamycin; (Cap), capecitabine; (Ox), oxaliplatin. * Significant differences between double combination compared with single treatments of each individual drug (P < 0.05). ** Significant differences of triple drug treated cases in compared to double combinations of each drugs (P < 0.05).