Cytotoxic and antitumor properties of methionine γ-lyase conjugate in combination with S-alk(en)yl–L-cysteine sulfoxides

Background. Enzyme prodrug therapy is a promising strategy to treat solid malignancies. The utilization of two-component systems, including an enzyme and a non-toxic prodrug, to generate cytotoxic compounds directly at the surface of the tumor cell can be successful strategy in reducing the overall toxic load on the body.

Aim. To determine antitumor activity of the pharmacological pair C115H methionine γ-lyase (C115H MGL) conjugated with daidzein (C115H MGL-Dz) and of S-alk(en)yl-L-cysteine sulfoxides against various types of solid tumors in vitro and in vivo.

Materials. MTT-test was used to determine the cytotoxicity of C115H MGL-Dz in the presence of S-alk(en)yl-L-cysteine sulfoxides in vitro against Sw620 (colon cancer), Panc1 (pancreatic cancer), and 22Rv1 (prostate cancer). Apopto- sis induction and cell cycle alteration in 22Rv1, Sw620, and SKBR3 cell lines were studied using the Muse® Caspase-3/7 and Muse® Cell Cycle Assay kits. In vivo anticancer activity was studied on Sw620, Panc1, and 22Rv1 subcutaneous xenografts in Balb/c nude mice.

Results. The C115H MGL-Dz had the maximum cytotoxic activity in the presence of S-propyl-L-cysteine sulfoxide (propiin) with IC₅₀ values: 3.88 and 5.4 for Panc1 and 22Rv1, respectively. Dipropyl thiosulfinate formed by the β-eli-mination of propiin catalyzed by C115H MGL-Dz, induces apoptosis through both the activation of caspases and alternative pathways, and also it inhibits cell division, contributing to a decrease in the concentration of cells in the G₂/M phase. The anticancer efficacy of the pharmacological pair C115H-Dz/propiin in vivo indicated a significant decrease in Panc1 tumor volume (tumor growth inhibition (TGI) 67.5 %, p = 0.004), Sw620 (TGI 22.07 %, p = 0.12) and 22Rv1 (TGI 70 %, p = 0.043).

Conclusion. Pharmacological pair C115H MGL-Dz/propiin was capable of suppressing tumor development in malignant solid tumors and might be considered as a potential anticancer approach in cancer prodrug therapy.