Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity

Journal of Pharmaceutical Analysis

Available online 9 February 2023

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CRCs with a non-angiogenic vascular phenotype respond poorly to chemotherapy in vivo.

Tumor cells induce endothelial apoptosis and vascular immaturity, thus limiting chemo-drug delivery.

By suppressing endothelial apoptosis, metformin sensitizes non-angiogenic CRCs to chemo-drug via the elevation of MVD and improvement of vascular maturity.

Endothelial apoptosis was mediated by the activation of Caspase signaling, which was abrogated by metformin administration.

Abstract

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer (CRC). In this study, we identified reduced microvessel density (MVD) and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance. We focused on the effect of metformin on MVD, vascular maturity and endothelial apoptosis of CRCs with a non-angiogenic phenotype, and further investigated its effect on overcoming chemoresistance. In situ transplanted cancer models were established to compare MVD, endothelial apoptosis and vascular maturity and function in tumors from metformin- and vehicle-treated mice. An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis. Transcriptome sequencing was performed for genetic screening. Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage, immaturity, reduced MVD and non-hypoxia. This phenomenon has also been observed in human CRC. Furthermore, non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro. By suppressing endothelial apoptosis, metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity. Further results showed that endothelial apoptosis was induced by tumor cells via activation of Caspase signaling, which was abrogated by metformin administration. These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC. By suppressing endothelial apoptosis, metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

Keywords

metformin

CRC

non-angiogenic

endothelial apoptosis

vascular immaturity

© 2023 The Author(s). Published by Elsevier B.V. on behalf of Xi’an Jiaotong University.

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