Diltiazem inhibits breast cancer metastasis via mediating growth differentiation factor 15 and epithelial-mesenchymal transition

Abstract

Migration and metastasis commonly happen to triple-negative breast cancer (TNBC) patients with advanced diseases. In many studies, it has been suggested that epithelial-mesenchymal transition (EMT) is one of the key mechanisms triggering cancer metastasis. Accumulating evidence has proven that calcium channel blockers mediate cell motility. Therefore, we attempt to investigate the effects of diltiazem, which has been selected from several FDA-approved clinical calcium channel blockers, on EMT in TNBC. By using both mouse and human TNBC cell lines, we found that diltiazem decreases colony formation and cell migration in breast cancer cells. The expression of epithelial markers such as E-cadherin and ZO-1 were increased dose-dependently by diltiazem, while mesenchymal markers such as Snail and Twist were decreased. In addition, we found that the expression of growth differentiation factor-15 (GDF-15) was also increased by diltiazem. Administering recombinant GDF-15 also reverses EMT, inhibits colony formation and migration in breast cancer cells. Moreover, treatment with diltiazem in tumor-bearing mice also decreases cancer metastasis and nodule formation, with more GDF-15 expression in diltiazem-treated mice than saline-treated mice, respectively. These findings suggest that diltiazem regulates EMT and cell motility through elevating GDF-15 expression in breast cancers in vitro and in vivo.

Aberrant expression of bone morphogenetic proteins in the disease progression and metastasis of breast cancer

“…On the other hand, a high level of GDF9 was associated with good progression in breast tissues (47). Interestingly, a recent study showed that Diltiazem, a calcium channel blocker, was able to prevent EMT and reduce migration and invasion of TNBC cancer cells by up-regulating GDF15, with GDF15 itself having the similar inhibitory effect on invasiveness and EMT (48). This is in line with the inverse correlation, between GDF15 and EMT markers, observed in the present study.…”

Repurposing Diltiazem for Its Neuroprotective Anti-Dementia Role against Intra-Cerebroventricular Streptozotocin-Induced Sporadic Alzheimer’s Disease-Type Rat Model

“…In this study, DTZ exhibited a beneficial role against the ICV-STZ-induced SAD rats in various aspects by attenuating the altered cognitive deficits, anti-oxidative defense parameters, pro-inflammatory cytokines, and APP expression. In experimental animal models, DTZ has been utilized in a variety of doses ranging from 5 mg/kg to 800 mg/kg for up to 10–40 days [ 57 , 58 , 59 ]. In this study, the treatment doses employed (10, 20, and 40 mg/kg) were selected after performing the pilot study and referring to the previous reports [ 29 ].…”

Repurposing Diltiazem for Its Neuroprotective Anti-dementia Role Against Intra-Cerebroventricular Streptozotocin-Induced Sporadic Alzheimer’s Disease-Type Rat Model

“…In this study, DTZ exhibited a beneficial role against the ICV-STZ-induced SAD rats in various aspects by attenuating the altered cognitive deficits, anti-oxidative defense parameters, pro-inflammatory cytokines, and APP expression. In experimental animal models, DTZ has been utilized in a variety of doses ranging from 5 mg/kg to 800 mg/kg for up to 10-40 days [57][58][59]. In this study, the treatment doses employed (10, 20, and 40 mg/kg) were selected after performing the pilot study and referring to the previous reports [29].…”