A novel biguanide derivative N-1-hexyl-N-5- (4-trifluoromethoxy) chloroguanidine in combination with sorafenib inhibits the proliferation of bladder cancer cells and its regulatory mechanism

ZHOU Xiaochen; HE Fanrong; WANG Weifan; XIE Yijun; XIAO Di; LI Duo; YANG Xiaoping

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Journal of Hunan Normal University(Medical Science) ›› 2025, Vol. 22 ›› Issue (3) : 1-7.

A novel biguanide derivative N-1-hexyl-N-5- (4-trifluoromethoxy) chloroguanidine in combination with sorafenib inhibits the proliferation of bladder cancer cells and its regulatory mechanism

ZHOU Xiaochen, HE Fanrong, WANG Weifan, XIE Yijun, XIAO Di, LI Duo, YANG Xiaoping

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Abstract

Objective Bladder cancer presents a significantly clinical challenge due to its high recurrence rate and the limited therapeutic options. Although Sorafenib has shown the promising clinical efficacy in liver cancer, its long-term use is often associated with adverse effect. Additionally, Metformin has demonstrated the potential in cancer therapy; however, its use with high doses may lead to side effect. This study is based on an intermediate derivatization strategy to design and synthesize a novel biguanide derivative, namely 6C, with the aim to evaluate its effect, as a monotherapy and in combination with Sorafenib, on bladder cancer cell proliferation and investigate its underlying mechanisms. Methods Firstly, the impact of 6C and Sorafenib alone on bladder cancer cell proliferation was assessed using the MTT assay. Subsequently, the effect of these drugs, both individually and in combination, on bladder cancer cell proliferation were further evaluated by colony formation assay. Finally, Western blotting was employed to examine the expression of epidermal growth factor receptor (EGFR) and autophagy-related proteins LC3-II and Beclin1 in bladder cancer cells by the treatment with 6C and Sorafenib combination therapy. Results Both 6C and Sorafenib alone significantly inhibited the proliferation of bladder cancer cells. The combination of 6C and Sorafenib exhibited a marked synergistic effect, demonstrating more potent inhibition of cell proliferation compared to either drug used alone. Mechanistic investigations revealed that the combination treatment significantly decreased the expression level of EGFR and upregulated the levels of autophagy markers LC3-II and Beclin1, thereby inducing autophagy of these cells. Conclusion The combination of 6C and Sorafenib decreases EGFR expression and induces autophagy, which inhibits bladder cancer cell proliferation. This study suggests that the combination therapy using 6C and Sorafenib may offer a novel therapeutic strategy with the promising application for bladder cancer treatment.

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bladder cancer / biguanide derivative / sorafenib / autophagy / combination therapy

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ZHOU Xiaochen, HE Fanrong, WANG Weifan, XIE Yijun, XIAO Di, LI Duo, YANG Xiaoping. A novel biguanide derivative N-1-hexyl-N-5- (4-trifluoromethoxy) chloroguanidine in combination with sorafenib inhibits the proliferation of bladder cancer cells and its regulatory mechanism[J]. Journal of Hunan Normal University(Medical Science). 2025, 22(3): 1-7

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