Strobilurin X acts as an anticancer drug by inhibiting protein synthesis and suppressing mitochondrial respiratory chain activity

Kenji Takahashi; Tomoya Tanaka; Atsushi Ishihara; Toshio Ohta

doi:10.1007/s12672-024-01041-w

Strobilurin X acts as an anticancer drug by inhibiting protein synthesis and suppressing mitochondrial respiratory chain activity

Discov Oncol. 2024 May 20;15(1):177. doi: 10.1007/s12672-024-01041-w.

Authors

Kenji Takahashi^{1

2}, Tomoya Tanaka³, Atsushi Ishihara⁴, Toshio Ohta^{5

6}

Affiliations

¹ Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan.
² Division of Functional Fungal Physiology and Pharmacology, Fungus/Mushroom Resource and Research Center, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan.
³ Graduate School of Sustainability Sciences, Tottori University, Tottori, 680-8553, Japan.
⁴ Division of Applied Fungal Chemistry, Fungus/Mushroom Resource and Research Center, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan.
⁵ Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan. tohta@tottori-u.ac.jp.
⁶ Division of Functional Fungal Physiology and Pharmacology, Fungus/Mushroom Resource and Research Center, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan. tohta@tottori-u.ac.jp.

Abstract

Purpose: Strobilurins act as antifungal agents by inhibiting the mitochondrial respiratory chain. The cytotoxic activity of strobilurins, focusing on its anticancer activities, has been reported. However, the mechanisms involved in these activities remain unclear.

Methods: The cytotoxic effects of strobilurin X isolated from the mycelium of Mucidula. venosolamellata were examined in human cancer cell lines (A549 and HeLa) and normal fibroblasts (WI-38).

Results: Strobilurin X significantly decreased the viability of A549 and HeLa cells compared to that in the WI-38 cells after 48 h of exposure. The EC₅₀ values for cytotoxicity in the A549, HeLa, and WI-38 cells were 3.4, 5.4, and 16.8 μg/mL, respectively. Strobilurin X inhibited the mitochondrial respiratory chain and enhanced the release of lactate in the A549 cells. The IC₅₀ value of strobilurin X against the mitochondrial respiratory chain complex III activity was 139.8 ng/mL. The cytotoxicity induced by strobilurin X was not completely rescued after adding uridine, methyl pyruvate, or N-acetyl cysteine. Furthermore, pharmacological approaches demonstrated that strobilurin X failed to modulate the mitogen-activated protein kinase family and phosphoinositide 3-kinase-Akt pathways; alternatively, it suppressed protein synthesis independent of uridine.

Conclusion: Strobilurin X induced cytotoxicity by blocking the mitochondrial respiratory chain and suppressing protein synthesis. These findings may aid in the development of novel anticancer drugs using strobilurins.

Keywords: Mucidula venosolamellata; Anticancer; Mitochondrial respiratory chain complex III; Protein synthesis; Strobilurin X.