Background: As the third confirmed gaseous transmitter, the role of
hydrogen sulfide (H2S) in the pathogenesis of multiple types of
cancer has been attracting increasing attention. Increased expression of
cystathionine β-synthase (CBS) and H2S in
colon cancer tissue samples has been validated and
tumor-derived H2S, mainly produced by CBS, stimulates bioenergetics, cell proliferation, and angiogenesis in
colon cancer. Recently, the therapeutic manipulation of H2S has been proposed as a promising anticancer approach. However, the effect of
aminooxyacetic acid (AOAA), which has been widely used as an inhibitor of CBS dependent synthesis of H2S, on the chemotherapeutic effect of
oxaliplatin (OXA) and the underlying mechanisms remain to be illustrated. Methods: We examined the expression of CBS in human
colorectal cancer specimens and matched normal mucosa by immunohistochemistry. The effect of AOAA on the sensitivity of
colon cancer cells to OXA and the level of apoptosis induced by
caspase cascade was investigated in both HCT116 and HT29 cell lines utilizing
CCK-8 assays, flow cytometry analysis and western blot analysis. The endogenous levels of
reactive oxygen species (ROS) were detected fluorescently by DCF-DA, and
glutathione (GSH) levels were measured by a Total GSH Detection Kit.
Tumor bearing xenograft mouse models and in vivo imaging systems were further used to investigate the effect of AOAA in vivo and immunohistochemistry (IHC) and TUNEL analysis were performed. Results: In the current study, we confirmed CBS, the main target of AOAA, is overexpressed in human
colorectal cancer by immunohistochemistry. The inhibitory effect of AOAA on the synthesis of H2S was validated utilizing
fluorescent probe and specific
electrode. AOAA significantly reduced the IC50 values of OXA in both
colon cancer cell lines. Co-incubation with AOAA elicited increased apoptosis induced by OXA, featured by increased activation of
caspase cascade. Besides, AOAA further increased the levels of ROS induced by OXA and attenuated the synthesis of
glutathione (GSH), which is a vital
antioxidant. Besides, the results of in vivo imaging and following IHC and TUNEL analysis were in accordance with cellular experiments, indicating that AOAA sensitizes
colon cancer cells to OXA via exaggerating intrinsic apoptosis. Conclusion: The results suggested that CBS is overexpressed in
colorectal cancer tissues and AOAA sensitizes
colon cancer cells to OXA via exaggerating apoptosis both in vitro and in vivo. Decreasing the endogenous level of GSH and consequently impaired detoxification of ROS might be one of the mechanisms underlying the effect of AOAA.