Anticancer Effects of Midazolam on Lung and Breast Cancers by Inhibiting Cell Proliferation and Epithelial-Mesenchymal Transition

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.

Drug Repurposing: The Mechanisms and Signaling Pathways of Anti-Cancer Effects of Anesthetics

“…Besides inhibiting cancer cell proliferation and induction of apoptosis, midazolam is also found to inhibit cancer cell invasion and metastasis. We and other labs have discovered that treatment of midazolam inhibits cancer cell proliferation, migration [ 39 , 40 ], invasion [ 39 , 40 ], and epithelial-mesenchymal transition [ 40 ]. These inhibitory effects of midazolam on cancer cell proliferation and metastasis are mediated by PBR, as the treatment of PBR antagonist reverses these inhibitory effects of midazolam [ 40 ].…”

“…We and other labs have discovered that treatment of midazolam inhibits cancer cell proliferation, migration [ 39 , 40 ], invasion [ 39 , 40 ], and epithelial-mesenchymal transition [ 40 ]. These inhibitory effects of midazolam on cancer cell proliferation and metastasis are mediated by PBR, as the treatment of PBR antagonist reverses these inhibitory effects of midazolam [ 40 ]. Seo et al discover that midazolam inhibits hyperglycemia-induced melanoma lung metastasis.…”

Tumor Progression, Microenvironments, and Therapeutics

“…Tumor malignancy starts from transformation [ 1 , 2 , 3 ], apoptotic suppression [ 4 ] tumor proliferation [ 5 , 6 , 7 ], followed by tumor progression [ 2 , 8 , 9 , 10 ], epithelial–mesenchymal transition (EMT), and tumor/metastasis-initiating stemness [ 6 , 11 , 12 ], with which the tumor microenvironments of primary tumor tissues are closely cross-talked [ 8 ]. Primary tumor cells then enter the bloodstream to become circulating tumor cells (CTCs) and colonize into distant organs to form secondary metastatic tumor tissues [ 4 , 13 , 14 ] that lead to cancer death [ 15 ].…”

“…Primary tumor cells then enter the bloodstream to become circulating tumor cells (CTCs) and colonize into distant organs to form secondary metastatic tumor tissues [ 4 , 13 , 14 ] that lead to cancer death [ 15 ]. Although numerous efforts, e.g., chemo-, radiation-, and target-therapies, have been made to kill tumor cells, the outcome of these therapeutic strategies often leads to distant relapse and increased patient mortality due to cancer stemness-mediated drug resistance and cancer metastasis [ 2 , 6 , 12 , 16 ]. Therefore, precise diagnosis [ 17 ] and alternative therapeutic strategies employing less cytotoxic drugs that may target various steps of tumor progression and tumor microenvironments [ 17 , 18 ] and circumvent unwanted adverse effects of drugs [ 14 , 19 ] are urgently needed.…”

“…During progression, the proliferation of tumor cells is promoted and apoptosis, including detached cell death anoikis, is suppressed. Lu et al repurposed Midazolam (MDZ), a common sedative drug acting through the γ-aminobutyric acid receptor in the central nervous system or benzodiazepine receptor (PBR) in peripheral tissues, to inhibit transforming growth factor β (TGF-β)-induced cancer cell proliferation, migration, invasion, and EMT mainly through PBR binding [ 6 ]. Their findings also unveiled a possibility that MDZ may potentially be effective in suppressing the growth of tumor-initiating cells, in that it inhibited the TGF-β-triggered Smad phosphorylation, a process that has been observed in mesenchymal stem cells, upon binding to PBR.…”