Abstract
Colon cancer cells contain high levels of cystathionine-beta-synthase (CBS). Its product, hydrogen sulfide (H2S) promotes the growth and proliferation of colorectal tumor cells. In order to improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we have designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171. YD0171 suppressed mitochondrial respiration and glycolytic function and induced G0/G1 arrest, but did not induce tumor cell apoptosis or necrosis. Metabolomic analysis in HCT116 cells showed that YD0171 affects multiple pathways of cell metabolism. The efficacy of YD0171 as an inhibitor of tumor growth was also tested in nude mice bearing subcutaneous HCT116 cancer cell xenografts. Animals were treated via subcutaneous injection of vehicle, AOAA (1, 3 or 9 mg/kg/day) or YD0171 (0.1, 0.5 or 1 mg/kg/day) for 3 weeks. Tumor growth was significantly reduced by 9 mg/kg/day AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/day. Thus, the in vivo efficacy of YD0171 is 9-times higher than that of AOAA. YD0171 (1 mg/kg/day) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/day) also reduced tumor growth in patient-derived tumor xenograft (PDTX) bearing athymic mice. YD0171 (3 mg/kg/day) induced the regression of established HCT116 tumors in vivo. A 5-day safety study in mice demonstrated that YD0171 at 20 mg/kg/day (given in two divided doses) does not increase plasma markers of organ injury, nor does it induce histological alterations in the liver or kidney. YD0171 caused a slight elevation in plasma homocysteine levels. In conclusion, the prodrug approach improves the pharmacological profile of AOAA; YD0171 represents a prototype for CBS inhibitory anticancer prodrugs. By targeting colorectal cancer bioenergetics, an emerging important hallmark of cancer, the approach exemplified herein may offer direct translational opportunities.
Highlights
Colorectal cancer remains the third most prevalent cancer in the United States, with over 49,000 estimated deaths in 2016 [1]
We show lower systemic toxicity with YD0171 administration compared with aminooxyacetic acid (AOAA) and demonstrate the translational therapeutic promise by inhibiting human colorectal cancer cell growth using patient-derived tumor xenografts
To begin developing YD0171 toward a potential anticancer therapeutic agent, we evaluated its efficacy using the human colon cancer cell line HCT116 and tissue xenografts in immune-compromised mice
Summary
Colorectal cancer remains the third most prevalent cancer in the United States, with over 49,000 estimated deaths in 2016 [1]. Over half of these patients are diagnosed with either regional nodal disease or distant organ metastasis, with a 5-year survival of 70% and 13%, respectively. Since not EFFICACY OF A CBS INHIBITOR PRODRUG all patients respond to, or have cancers that are appropriate for treatment with standard and available therapies, novel targeted therapeutic options are needed. The prototypical CBS inhibitor aminooxyacetic acid (AOAA) suppresses the proliferation of colon cancer cells in vitro and reduces tumor growth in vivo [1,2]. CBS and H2S have been implicated in the pathogenesis of ovarian and breast cancer [6,7]
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