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

Guang-Yue Li; Shu-Jing Zhang; Dong Xue; Yue-Qi Feng; Yan Li; Xun Huang; Qiang Cui; Bo Wang; Jun Feng; Tao Bao; Pei-Jun Liu; Shao-Ying Lu; Ji-Chang Wang

doi:10.1016/j.jpha.2023.02.001

Volume 13 Issue 3

Mar. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(3): 262-275

Guang-Yue Li, Shu-Jing Zhang, Dong Xue, Yue-Qi Feng, Yan Li, Xun Huang, Qiang Cui, Bo Wang, Jun Feng, Tao Bao, Pei-Jun Liu, Shao-Ying Lu, Ji-Chang Wang. Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity[J]. Journal of Pharmaceutical Analysis, 2023, 13(3): 262-275. doi: 10.1016/j.jpha.2023.02.001

Citation:

Guang-Yue Li, Shu-Jing Zhang, Dong Xue, Yue-Qi Feng, Yan Li, Xun Huang, Qiang Cui, Bo Wang, Jun Feng, Tao Bao, Pei-Jun Liu, Shao-Ying Lu, Ji-Chang Wang. Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity[J]. Journal of Pharmaceutical Analysis, 2023, 13(3): 262-275. doi: 10.1016/j.jpha.2023.02.001

Citation:

Guang-Yue Li, Shu-Jing Zhang, Dong Xue, Yue-Qi Feng, Yan Li, Xun Huang, Qiang Cui, Bo Wang, Jun Feng, Tao Bao, Pei-Jun Liu, Shao-Ying Lu, Ji-Chang Wang. Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity[J]. Journal of Pharmaceutical Analysis, 2023, 13(3): 262-275. doi: 10.1016/j.jpha.2023.02.001

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

doi: 10.1016/j.jpha.2023.02.001

a. Department of Science and Technology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China;
b. Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China;
c. Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China;
d. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China;
e. Department of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China

Funds:

This work was financially supported by grants from the National Natural Science Foundation of China (Grant No.: 81972811), the Key Research and Development Foundation of Shaanxi Province (Grant Nos.: 2018SF-099, S2021SF-136, 2021JM-273, and 2022JQ-848), the Fundamental Research Funds for the Central Universities (Grant No.: xzy012022094), and the Provincial Science and Technology Rising Star (Grant No.: 2021KJXX-03).

Received Date: Sep. 10, 2022
Accepted Date: Feb. 01, 2023
Rev Recd Date: Jan. 12, 2023
Publish Date: Feb. 09, 2023

Abstract

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 in 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 had 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.
- Metformin,
- Colorectal cancer,
- Non-angiogenic,
- Endothelial apoptosis,
- Vascular immaturity

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References(49)

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