Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells

Abstract

This study examined the signaling events induced by shikonin that lead to the induction of apoptosis in Bcr/ Abl-positive chronic myelogenous leukemia (CML) cells (e.g., K562, LAMA84). Treatment of K562 cells with shikonin (e.g., 0.5 μM) resulted in profound induction of apoptosis accompanied by rapid generation of reactive oxygen species (ROS), striking activation of c-Jun-N-terminal kinase (JNK) and p38, marked release of the mitochondrial proteins cytochrome c and Smac/DIABLO, activation of caspase-9 and -3, and cleavage of PARP. Scavenging of ROS completely blocked all of the above-mentioned events (i.e., JNK and p38 phosphorylation, cytochrome c and Smac/DIABLO release, caspase and PARP cleavage, as well as the induction of apoptosis) following shikonin treatment. Inhibition of JNK and knock-down of JNK1 significantly attenuated cytochrome c release, caspase cleavage and apoptosis, but did not affect shikonin-mediated ROS production. Additionally, inhibition of caspase activation completely blocked shikonin-induced apoptosis, but did not appreciably modify shikonin-mediated cytochrome c release or ROS generation. Altogether, these findings demonstrate that shikonin-induced oxidative injury operates at a proximal point in apoptotic signaling cascades, and subsequently activates the stress-related JNK pathway, triggers mitochondrial dysfunction, cytochrome c release, and caspase activation, and leads to apoptosis. Our data also suggest that shikonin may be a promising agent for the treatment of CML, as a generator of ROS.

MAPK inhibitors differentially affect gallic acid-induced human pulmonary fibroblast cell growth inhibition

“…Therefore, the anti-or pro-apoptotic effects of the MeK inhibitor on Ga-treated lung cells can be variable depending on cell type. in general, the activation of JnK or p38 leads to apoptosis (13)(14)(15). in fact, the JnK inhibitor was found to protect Pc12 rat phenochromocytoma against Ga-induced cell death (25), and the p38 inhibitor was found to decrease the death of pyrogallol-induced calf pulmonary artery endothelial cells (20).…”

“…The mitogen-activated protein kinases (MaPKs) are involved in cell proliferation, differentiation and cell death (12). Substantial evidence demonstrates that the c-Jun n-terminal kinase/stress-activated protein kinase (JnK/SaPK) and p38 are activated by roS, and oxidative stress leads to apoptosis (13)(14)(15). roS also are known to regulate the activation of the extracellular signal regulated kinase (erK1/2)-activating kinase (MeK) and erK (16,17).…”

The MEK inhibitor PD98059 attenuates growth inhibition and death in gallic acid-treated Calu-6 lung cancer cells by preventing glutathione depletion

“…This indirectly suggests that the inhibition of erK signaling by MeK inhibitor plays a pro-survival role in Ga-treated calu-6 cells. Multiple lines of evidence demonstrate that JnK or p38 signaling is related to cell death (16,17). indeed, Ga was shown to induce Pc12 rat phenochromocytoma cell death through the activation of JnK, and JnK inhibitor protected Pc12 cells against Ga-induced cell death (25).…”

“…each MaP kinase pathway has relatively different upstream activators and specific substrates (15). Multiple lines of evidence demonstrate that JnK and p38 are strongly activated by roS or by a mild oxidative shift in the intracellular thiol/disulfide redox state, leading to apoptosis (16,17). roS are also known to induce erK phosphorylation and to activate the erK pathway (18).…”

Penta-O-galloyl-beta-D-glucose enhances antitumor activity of imatinib and suppresses the growth of K562 cells in mice

“…For instance, Mao et al (2008) reported that shikonin induced apoptosis through the ROS/ c-Jun N-terminal kinases (JNK)-mediated process in CML cell lines K562 and LAMA84. Rakshit et al (2010) reported the role of ROS in chlorogenic acid (Chi)-induced cell death in CML cell lines as well as primary leukemia cells from CML patients.…”