Cytotoxic and Anticancer Activity of Pharmacological Pairs of C115H Methionine–Gamma-lyase and S-Propyl-L-Cysteine Sulfoxide

Abstract

BACKGROUND: One of the alternate ways to developing novel medication is to use pharmacological pairs: an enzyme and a non-toxic prodrug that, under certain conditions, releases cytotoxic substances within or on the surface of the cancer cells, allowing the drug to be delivered precisely to the cancer cells.

AIM: To evaluate cytotoxic and anticancer effects of the pharmacological pair of C115H methionine-γ-lyase (C115H MGL), conjugated with daidzein (C115H MGL-Dz), and S-propyl-L-cysteine sulfoxide (propiin) against different kinds of solid tumors in vitro and in vivo.

METHODS: MTT-test was performed to determine the cytotoxicity of C115H MGL-Dz in the presence of propiin in vitro against human embryonic kidney (HEK-293), human placenta, breast cancer (MCF7, SKBR3, and T47D), colon cancer (HT29 and COLO205), pancreatic cancer (MIA PaCa-2) and prostate cancer (DU145, and PC3) cells. The anticancer activity of the pharmacological pair "C115H MGL-Dz + propiin" against SKBR3, MIA PaCa-2, and HT29 in vivo was investigated using subcutaneous xenografts in BALB/c nude mice.

RESULTS: In comparison to dipropylthiosulfinate generated in vitro using the pharmacological pairs "C115H MGL + propiin", targeted delivery of C115H MGL-Dz as a component of a pharmacological pair "C115H MGL-Dz + propiin" to generate dipropylthiosulfinate directly on the surface of cancer cells enhances cytotoxicity in all cancer cells. The study of the antitumor activity of the pharmacological pair "C115H MGL-Dz + propiin" in vivo revealed a suppression of tumor volume growth in xenografts SKBR3 (tumor growth inhibition, TGI=89%, p=0.004), MIA PaCa-2 (TGI=50%, p=0.011), and HT29 (TGI=52%, p=0.04) vs control.

CONCLUSIONS: On several cancer cells, the cytotoxicity and anticancer activity of dipropylthiosulfinate produced by the pharmacological pair "C115H MGL-Dz + propiin" was observed. Our findings may stimulate more study into the role of pharmacological pairs as a novel strategy to cancer treatment.

Keywords

enzyme prodrug therapy / methionine γ-lyase / drug targeting / thiosulfinates

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Funding

Государственная программа Министерства науки и высшего образования РФState Program of the Ministry of Science and Higher Education of the Russian Federation(075-01551-23-00; FSSF-2023-0006)

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