Azithromycin Synergistically Enhances Anti-Proliferative Activity of Vincristine in Cervical and Gastric Cancer Cells

Xuezhang Zhou,Yong Li,Xiaoming Liu,Xiujing Hao,Yuyan Zhang,Yujiong Wang

doi:10.3390/cancers4041318

Abstract

In this study, the anti-proliferative and anticancer activity of azithromycin (AZM) was examined. In the presence of AZM, cell growth was inhibited more effectively in Hela and SGC-7901 cancer cells, relative to transformed BHK-21 cells. The respective 50% inhibition of cell growth (IC50) values for Hela, SGC-7901 and BHK-21 were 15.66, 26.05 and 91.00 µg/mL at 72 h post incubation, indicative of a selective cytotoxicity against cancer cells. Cell apoptosis analysis using Hoechst nuclear staining and annexin V-FITC binding assay further demonstrated that AZM was capable of inducing apoptosis in both cancer cells and transformed cells. The apoptosis induced by AZM was partly through a caspase-dependent mechanism with an up-regulation of apoptotic protein cleavage PARP and caspase-3 products, as well as a down-regulation of anti-apoptotic proteins, Mcl-1, bcl-2 and bcl-X1. More importantly, a combination of AZM and a low dose of the common anti-cancer chemotherapeutic agent vincristine (VCR), produced a selectively synergistic effect on apoptosis of Hela and SGC-7901 cells, but not BHK-21 cells. In the presence of 12.50 μg/mL of VCR, the respective IC50 values of Hela, SGC-7901 and BHK-21 cells to AZM were reduced to 9.47 µg/mL, 8.43 µg/mL and 40.15 µg/mL at 72 h after the incubation, suggesting that the cytotoxicity of AZM had a selective anti-cancer effect on cancer over transformed cells in vitro. These results imply that AZM may be a potential anticancer agent for use in chemotherapy regimens, and it may minimize side effects via reduction of dosage and enhancing the effectiveness common chemotherapeutic drugs.

Highlights

Antibiotics are generally thought to be safe agents with trivial or no side effects, since they typically use unique molecular targets against microorganisms
An MTT viability assay was performed to determine the anti-proliferative activity of AZM and VCR in cancer cells by evaluating the inhibition of cell growth
SGC-7901 and BHK-21 cells were incubated with different doses of AZM (A) and VCR (B) for indicated time periods

Summary

Introduction

Antibiotics are generally thought to be safe agents with trivial or no side effects, since they typically use unique molecular targets against microorganisms Aside from their anti-microbial activity properties, several classes of antibiotics display an ability to induce cell apoptosis, which is believed to be an important property of any potential anti-cancer drug [1,2,3,4,5]. Azithromycin (AZM), a 15-ring member macrolide antibiotic, differs from other macrolides known to inhibit cytochrome P450 (CYP) 3A4 [6] This unique metabolic feature leads AZM to possess the favorable property of rapidly accumulating and slowly releasing into cells and tissues, resulting in a higher local concentration of drug, and a longer elimination half-life [7]. The effect of AZM on cancer cell apoptosis and its interactions with commonly used anti-cancer agents have not been investigated yet

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