Abstract
Despite improvements in cancer treatments resulting in higher survival rates, the proliferation and metastasis of tumors still raise new questions in cancer therapy. Therefore, new drugs and strategies are still needed. Midazolam (MDZ) is a common sedative drug acting through the γ-aminobutyric acid receptor in the central nervous system and also binds to the peripheral benzodiazepine receptor (PBR) in peripheral tissues. Previous studies have shown that MDZ inhibits cancer cell proliferation but increases cancer cell apoptosis through different mechanisms. In this study, we investigated the possible anticancer mechanisms of MDZ on different cancer cell types. MDZ inhibited transforming growth factor β (TGF-β)-induced cancer cell proliferation of both A549 and MCF-7 cells. MDZ also inhibited TGF-β-induced cell migration, invasion, epithelial-mesenchymal-transition, and Smad phosphorylation in both cancer cell lines. Inhibition of PBR by PK11195 rescued the MDZ-inhibited cell proliferation, suggesting that MDZ worked through PBR to inhibit TGF-β pathway. Furthermore, MDZ inhibited proliferation, migration, invasion and levels of mesenchymal proteins in MDA-MD-231 triple-negative breast cancer cells. Together, MDZ inhibits cancer cell proliferation both in epithelial and mesenchymal types and EMT, indicating an important role for MDZ as a candidate to treat lung and breast cancers.
Highlights
There were more than 19.3 million new cancer cases and 10 million cancer deaths that occurred in 2020 [1]
The results showed that transforming growth factor-β (TGF-β) significantly increased A549 cells proliferation compared to the control, whereas treatment with MDZ (10 μM) alone showed no effect on A549 cell proliferation
It has been suggested that TGF-β is a potent inducer of epithelial-mesenchymal transition (EMT) in cancer [28], and our results showed that MDZ inhibited TGF-β-induced migration and invasion of both A549 and MCF-7 cells
Summary
There were more than 19.3 million new cancer cases and 10 million cancer deaths that occurred in 2020 [1]. There exist a number of challenges to the treatment of cancer, in particular achieving an understanding of the diverse mechanisms underlying the proliferation and metastasis of cancer cells. The ability of these cells to survive beyond normal life span and to proliferate abnormally has been a major focus of the research into finding appropriate anti-cancer drugs [2]. TGF-β acts as a tumor promoter in several cancer types due to mutations that taken place during cancer proliferation. This may lead to resistance to the growth inhibitory effects of TGF-β and eventually promote tumorigenesis, increases in metastasis and chemo resistance [5,6]
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