Triptolide induces apoptosis in human leukemia cells through caspase-3-mediated ROCK1 activation and MLC phosphorylation

Abstract

The diterpene triepoxide triptolide is a major active component of Tripterygium wilfordii Hook F, a popular Chinese herbal medicine with the potential to treat hematologic malignancies. In this study, we investigated the roles of triptolide in apoptosis and cell signaling events in human leukemia cell lines and primary human leukemia blasts. Triptolide selectively induced caspase-dependent cell death that was accompanied by the loss of mitochondrial membrane potential, cytochrome c release, and Bax translocation from the cytosol to the mitochondria. Furthermore, we found that triptolide dramatically induced ROCK1 cleavage/activation and MLC and MYPT phosphorylation. ROCK1 was cleaved and activated by caspase-3, rather than RhoA. Inhibiting MLC phosphorylation by ML-7 significantly attenuated triptolide-mediated apoptosis, caspase activation, and cytochrome c release. In addition, ROCK1 inhibition also abrogated MLC and MYPT phosphorylation. Our in vivo study showed that both ROCK1 activation and MLC phosphorylation were associated with the tumor growth inhibition caused by triptolide in mouse leukemia xenograft models. Collectively, these findings suggest that triptolide-mediated ROCK1 activation and MLC phosphorylation may be a novel therapeutic strategy for treating hematological malignancies.

Polyphenols from brown alga, Padina boergesenii (Allendar & Kraft) decelerates renal cancer growth involving cell cycle arrest and induction of apoptosis in renal carcinoma cells

“…The active fraction have inhibited cell proliferation greatly through reducing yellow color tetrazolium salt in to a dark blue/purple product of cellular mitochondrial dehydrogenase enzyme in living cells . Inhibition of cytosolic compartment of cell proliferation at different time‐point in renal carcinoma cells were in accordance with previous reports .…”

<p>NMMHC IIA Inhibition Ameliorates Cerebral Ischemic/Reperfusion-Induced Neuronal Apoptosis Through Caspase-3/ROCK1/MLC Pathway</p>

“…37 Moreover, caspase-3/ROCK1/MLC has also been proved to be a novel cyclic positive feedback loop for regulating apoptosis in different cell types, such as cardiac myocyte, human leukemia cells and neurons. [40][41][42] We have previously reported the caspase-3/ROCK1/MLC feedback loop in H 2 O 2induced PC12 cell injury, and NMMHC IIA is also involved in a positive feedback loop that links caspase-3/ROCK1/MLC signaling axis. 13,22 Our present findings confirmed that I/ R-induced caspase-3 cleavage led to decrease of ROCK1 and MLC phosphorylation.…”

Triptolide inhibits cell growth and GRP78 protein expression but induces cell apoptosis in original and radioresistant NPC cells

“…TPL has been found to sensitize cancer cells to apoptosis [16–18]. Moreover, a recent study reported that the expression of GRP78 in pancreatic cancer cell lines is downregulated by TPL, leading to cell apoptosis and autophagy [19].…”