2‐methoxyestradiol inhibits atorvastatin‐induced rounding of human vascular smooth muscle cells

Abstract

The cardiovascular benefits of statins, including atorvastatin (ATV), have been reported to be gender-dependent, but the underlying mechanism is unclear. In this study we examine whether estrogen and its metabolite, 2-methoxyestradiol (2ME), affect the rounding response of human vascular smooth muscle cells (SMCs) induced by ATV. Twenty-four hour treatment with ATV (10-100 microM) induced rounding of cultured human SMCs. Addition of 2ME (1-20 microM), but not 17beta-estradiol, for 2 h induced re-spreading of rounded cells. Our further studies showed that the effects of 2ME were mimicked by microtubule-disrupting drugs and inhibited by taxol. Inhibition of RhoA and ROCK (Rho-kinase) by C3-toxin and H-1152, respectively, blocked 2ME effects. 2ME effects were also blocked by treatment with either actin-interfering drugs, such as cytochalasin D and jasplakinolide, or myosin inhibitor blebbistatin. ML-7 and -9, the inhibitors for myosin light chain kinase, inhibited 2ME effect as well. ATV treatment induced a decrease of F-actin content and Thr18/Ser19 dual phosphorylation of myosin regulatory light chain (MRLC), which was rescued by 2ME or mevalonate. The rescue effects of 2ME on F-actin content and MRLC dual phosphorylation were abolished by taxol or H-1152. In addition, kinesin Eg5 inhibitor monastrol and dynein inhibitor erythro-9-3-(2-hydroxynonyl) adenine (EHNA) significantly blocked 2ME effects. Finally, our results revealed that 2ME inhibited the migration of SMCs induced by ATV (0.1 microM) in wound healing assay and Boyden chamber assay. In summary, our data show that 2ME, but not estrogen, inhibits ATV-induced rounding of human SMCs through induction of microtubule disassembly and activation of the Rho-ROCK-actinomyosin pathway.

2‐methoxyestradiol impacts on amino acids‐mediated metabolic reprogramming in osteosarcoma cells by its interaction with NMDA receptor

“…Importantly, 2‐ME when used at physiological and pharmacological conditions, was potent enough to reverse the migration and proliferation of osteosarcoma cells induced by low concentrations of D‐serine and glycine. The anti‐migrative potential of 2‐ME was previously demonstrated (Wu et al, ; Yin et al, ). Similarly to our study, Yin and colleagues evaluated using wound healing assay that 2‐ME at micromolar concentrations inhibits the migration of human vascular smooth muscle cells (Yin et al, ).…”

“…The anti‐migrative potential of 2‐ME was previously demonstrated (Wu et al, ; Yin et al, ). Similarly to our study, Yin and colleagues evaluated using wound healing assay that 2‐ME at micromolar concentrations inhibits the migration of human vascular smooth muscle cells (Yin et al, ). The obtained data confirmed that 2‐ME may be considered as a physiological anticancer molecule (Gorska et al, ; Gorska, Kuban‐Jankowska et al, ).…”

“…Metastatic migratory power of osteosarcoma 143B was investigated in vitro model using the wound healing migration assay (Bruns et al, ; Wu et al, ; Yin, Gui, & Zheng, ). The cells were seeded onto six‐well plates at a density of 1 × 10 6 cells/well and incubated 24 hr until the cells reached 90% confluency.…”

The Tumor Suppressor, p190RhoGAP, Differentially Initiates Apoptosis and Confers Docetaxel Sensitivity to Breast Cancer Cells

“…42 Additionally, a myosin II inhibitor stabilized microtubules, 42 prompting investigators to look at the role of myosin II in MT regulation. They found that cells treated with MT destabilizing drugs exhibited an increase in rMLC phosphorylation, 43 while Taxol treatment abolished rMLC phosphorylation, 48 suggesting that MT organization is regulated through a Rho/ROCK/myosin II pathway. Our work shows that the sensitivity of MDA-MB-468 and MDA-MB-231 breast cancer cells to docetaxel-induced apoptosis is modulated through Rho and p190, possibly through the ROCK and rMLC pathway.…”

Recent Advances in chemistry and pharmacology of 2-methoxyestradiol: An anticancer investigational drug

“…It also inhibits smooth muscle contraction through endothelial NO release [181]. Yin et al demonstrated that cardioprotective effect of 2ME 2 is through the involvement of the integrindependent signalling, Ca 2+ mobilization, release of ROS, cAMP-PKA pathway and unspecified protein kinases/phosphatises in inhibiting atorvastatin induced human vascular smooth muscle cell rounding [182]. There are several other reports of inhibition of rat aortic smooth muscle contraction by 2ME 2 [183].…”