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ABSTRACT: Necrostatin-1 (Nec-1) inhibits necroptosis by allosterically inhibiting the kinase activity of receptor-interacting protein 1 (RIP1), which plays a critical role in necroptosis. RIP1 is a crucial adaptor kinase involved in the activation of NF-κB, production of reactive oxygen species (ROS) and the phosphorylation of mitogen activated protein kinases (MAPKs). NF-κB, ROS and MAPKs all play important roles in apoptotic signaling. Nec-1 was regarded as having no effect on apoptosis. Here, we report that Nec-1 increased the rate of nuclear condensation and caspases activation induced by a low concentration of shikonin (SHK) in HL60, K562 and primary leukemia cells. siRNA-mediated knockdown of RIP1 significantly enhanced shikonin-induced apoptosis in K562 and HL60 cells. Shikonin treatment alone could slightly inhibit the phosphorylation of ERK1/2 in leukemia cells, and the inhibitory effect on ERK1/2 was significantly augmented by Nec-1. We also found that Nec-1 could inhibit NF-κB p65 translocation to the nucleus at a later stage of SHK treatment. In conclusion, we found that Nec-1 can promote shikonin-induced apoptosis in leukemia cells. The mechanism by which Nec-1 sensitizes shikonin-induced apoptosis appears to be the inhibition of RIP1 kinase-dependent phosphorylation of ERK1/2. To our knowledge, this is the first study to document Nec-1 sensitizes cancer cells to apoptosis.
International Journal of Molecular Sciences 01/2012; 13(6):7212-25. · 2.60 Impact Factor
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ABSTRACT: As a nature phytoalexin found in grapes, resveratrol has been proposed as a potential drug for cancer chemoprevention and treatment. However, its poor bioavailability limits its potential clinical application. Pterostilbene, the natural dimethylated analog of resveratrol with greater bioavailability, was confirmed to inhibit tumor growth both in vivo and in vitro, demonstrating its potential for further clinical application. In the current study, we found that pterostilbene could markedly inhibit the growth of two independent breast cancer cell lines. Both apoptosis and cell cycle arrest as well as the inhibition of wnt singling was induced by pterostilbene. The dominant-active mutant of β-catenin could reverse the growth inhibitory effect of pterostilbene, indicating that the inhibition of wnt signaling is important to the growth inhibitory effect of pterostilbene. Interestingly, pterostilbene induced autophagy and blockage of autophagy augmented pterostilbene-induced growth inhibition, suggesting that the combination of autophagy inhibitors with pterostilbene and other therapeutics such as endocrine drugs could serve as a new and promising strategy for the treatment of breast cancer cells.
American Journal of Translational Research 01/2012; 4(1):44-51.
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Weidong Han,
Jie Sun,
Lifeng Feng,
KaiFeng Wang,
Da Li,
Qin Pan,
Yan Chen,
Wei Jin,
Xian Wang,
Hongming Pan,
Hongchuan Jin
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ABSTRACT: Anthracycline daunorubicin (DNR) is one of the major antitumor agents widely used in the treatment of myeloid leukemia. Unfortunately, the clinical efficacy of DNR was limited because of its cytotoxity at high dosage. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether DNR can activate to impair the sensitivity of cancer cells remains unknown. Here, we first report that DNR can induce a high level of autophagy, which was associated with the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Moreover, cell death induced by DNR was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting Atg5 and Atg7, the most important components for the formation of autophagosome. In conclusion, we found that DNR can induce cytoprotective autophagy by activation of ERK in myeloid leukemia cells. Autophagy inhibition thus represents a promising approach to improve the efficacy of DNR in the treatment of patients with myeloid leukemia.
PLoS ONE 01/2011; 6(12):e28491. · 4.09 Impact Factor
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Weidong Han,
Hongming Pan,
Yan Chen,
Jie Sun,
Yanshan Wang,
Jing Li,
Weiting Ge,
Lifeng Feng,
Xiaoying Lin,
Xiaojia Wang,
Xian Wang,
Hongchuan Jin
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ABSTRACT: Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer.
PLoS ONE 01/2011; 6(6):e18691. · 4.09 Impact Factor
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ABSTRACT: Degterev et al. previously demonstrated that death receptor mediated apoptosis could be diverted to necroptosis when apoptosis signaling was blocked, suggesting that necroptosis may function as a backup mechanism to insure the elimination of damaged cells under certain conditions when apoptosis was inhibited. Here, we show that shikonin-induced necroptosis can be reverted to apoptosis in the presence of necrostatin-1 (Nec-1), a specific necroptosis inhibitor and that the death mode switch is at least partially due to the conversion from mitochondrial inner membrane permeability to mitochondrial outer membrane permeability, which is associated with Bax translocation. The data combined with the previous reports support a notion that apoptosis and necroptosis may function as reciprocal backup mechanisms of cellular demise. To the best of our knowledge, this is the first study to document a conversion from necroptosis to apoptosis.
Apoptosis 04/2009; 14(5):674-86. · 4.07 Impact Factor
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ABSTRACT: The dose-cumulative cardiotoxicities and the emerging cancerous apoptotic/drug resistance are two major obstacles limiting the efficacy of anthracycline antibiotics, notably doxorubicin. We attempted to prove if schisandrin B (Sch B), a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1, could protect against doxorubicin-induced cardiotoxicity, on the premise that Sch B is an enhancer of glutathione redox cycling that may attenuate doxorubicin-induced oxidative stress in the cardiomyocytes.
Mice or rat were dosed with a single injection of doxorubicin (25 mg/kg, i.p.) with or without pretreatment of Sch B. The protective roles of Sch B against doxorubicin-induced cardiac damage were evaluated on the aspects of the release of cardiac enzymes into serum, the formation of malondialdehyde, the activation of matrix metalloproteinase, the structural damage in the left ventricles, the mortality rates, and the cardiac functions.
Pretreatment of Sch B significantly attenuated doxorubicin-induced cardiotoxicities on all the aspects listed above. The underlying mechanism was associated with the effect of Sch B on maintaining the cardiomyocytic glutathione and the activities of superoxide dismutase, and the key enzymes (glutathione peroxidase, glutathione reductase, and glutathione transferase) responsible for glutathione redox cycling, which neutralized doxorubicin-induced oxidative stress.
To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1, which is potentially applicable to treat cancers, especially the multidrug-resistant cancers involving doxorubicin or its kin.
Clinical Cancer Research 12/2007; 13(22 Pt 1):6753-60. · 7.74 Impact Factor
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ABSTRACT: Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b) loss of plasma membrane integrity; (c) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-x(L), which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance.
Molecular Cancer Therapeutics 06/2007; 6(5):1641-9. · 5.23 Impact Factor
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ABSTRACT: Previous reports have shown that honokiol induces apoptosis in numerous cancer cell lines and showed preclinical efficacies against apoptosis-resistant B-cell chronic lymphocytic leukemia and multiple myeloma cells from relapse-refractory patients. Here, we show that honokiol can induce a cell death distinct from apoptosis in HL60, MCF-7, and HEK293 cell lines. The death was characterized by a rapid loss of integrity of plasma membrane without externalization of phosphatidyl serine. The broad caspase inhibitor z-VAD-fmk failed to prevent this cell death. Consistently, caspase activation and DNA laddering were not observed. The death was paralleled by a rapid loss of mitochondrial membrane potential, which was mechanistically associated with the mitochondrial permeability transition pore regulated by cyclophilin D (CypD) based on the following evidence: (a) cyclosporin A, an inhibitor of CypD (an essential component of the mitochondrial permeability transition pore), effectively prevented honokiol-induced cell death and loss of mitochondrial membrane potential; (b) inhibition of CypD by RNA interference blocked honokiol-induced cell death; (c) CypD up-regulated by honokiol was correlated with the death rates in HL60, but not in K562 cells, which underwent apoptosis after being exposed to honokiol. We further showed that honokiol induced a CypD-regulated death in primary human acute myelogenous leukemia cells, overcame Bcl-2 and Bcl-X(L)-mediated apoptotic resistance, and was effective against HL60 cells in a pilot in vivo study. To the best of our knowledge, this is the first report to document an induction of mitochondrial permeability transition pore-associated cell death by honokiol.
Cancer Research 06/2007; 67(10):4894-903. · 7.86 Impact Factor
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ABSTRACT: A bacterial strain HLK1(T) was isolated from the human erythroleukemia cell line K562. This bacterium is a Gram-negative rod, motile with a polar flagellum. It is strictly aerobic, nonfermentative, and oxidase and catalase positive. Its optimal growth occurs at 37 degrees C at pH between 6.5 and 7.5. Phylogenetically, although it shares 98% similarity with the 16S rRNA of Phenylobacterium lituiforme, the DNA-DNA hybridization value between the two species is only 43%. HLK1(T) has a DNA G+C content of 71.2+/-0.2 mol%. It is a facultative intracellular organism and may have pathogenic relevance with humans and mammals. On the basis of the phylogenetic and phenotypic characterization, strain HLK1(T) is proposed to be classified in the genus Phenylobacterium, as P. zucineum sp. nov. The type strain is HLK1(T) (=CGMCC 1.3786(T), DSM=18354).
Systematic and Applied Microbiology 05/2007; 30(3):207-12. · 3.37 Impact Factor
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ABSTRACT: Targeting the "weak point" of cancers, especially the apoptotic/drug resistant cancers, is critical for the success of cancer chemotherapy. We found that the drug resistant cancer cell lines overexpressing P-gp, MRP1, BCRP, Bcl-2 and Bcl-xL are susceptible to shikonin, a necroptotic inducer, despite the fact that they are highly resistant to a variety of anticancer agents such as anthracycline antibiotics, vinca alkaloids, taxanes, epipodophylotoxins, etc. These findings reveal that, although apoptotic/drug resistance is a formidable "stronghold" of cancer against chemotherapy, necroptotic susceptibility is an intrinsic "weak point" of cancer. Therefore, targeting the weakness of cancer by induction of necroptosis may have significant potential in cancer chemotherapy, especially in the apoptotic/drug resistant cancers.
Autophagy 3(5):490-2. · 7.45 Impact Factor
