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Theranostics

Theranostics

IF: 13.3
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Compensatory combination of mTOR and TrxR inhibitors to cause oxidative stress and regression of tumors

Published:25 February 2021 DOI: 10.7150/thno.52077 PMID: 33754064
Yiqun Xia, Jundixia Chen, Yun Yu, Fengjiao Wu, Xin Shen, Chenyu Qiu, Tingting Zhang, Lin Hong, Peisen Zheng, Rongrong Shao, Chenxin Xu, Fang Wu, Wei Chen, Congying Xie, Ri Cui, Peng Zou

Abstract

Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.

Substances (16)

Materials
Procduct Name CAS Molecular Formula Supplier Price
3-METHYLADENINE 5142-23-4 C6H7N5 392 suppliers $12.00-$1890.00
3-METHYLADENINE 5142-23-4 C6H7N5 392 suppliers $12.00-$1890.00
3-METHYLADENINE 5142-23-4 C6H7N5 392 suppliers $12.00-$1890.00
3-METHYLADENINE 5142-23-4 C6H7N5 392 suppliers $12.00-$1890.00
AZD-8055 1009298-09-2 C25H31N5O4 233 suppliers $12.00-$2770.00
AZD-8055 1009298-09-2 C25H31N5O4 233 suppliers $12.00-$2770.00
AZD-8055 1009298-09-2 C25H31N5O4 233 suppliers $12.00-$2770.00
AZD-8055 1009298-09-2 C25H31N5O4 233 suppliers $12.00-$2770.00
Auranofin 34031-32-8 C20H34AuO9PS 196 suppliers $45.00-$2290.00
Auranofin 34031-32-8 C20H34AuO9PS 196 suppliers $45.00-$2290.00

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