Cyclosporin A does not protect the disruption of the inner mitochondrial membrane potential induced by potassium ionophores in intact K562 cells

Marques‐Santos, Luis Fernando; Coqueiro, Vivian M.; Rumjanek, Vivian M.

doi:10.1016/j.cellbi.2005.10.021

Cited by 15 publications

(13 citation statements)

References 39 publications

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“…MPT inhibitors have become useful tools in the study of the processes of cell death in relation to mitochondrial physiology. One of the most employed inhibitors is cyclosporine A (CSA) (Marques-Santos et al, 2006). The observation that CSA did not protect HL60 cells against the cytotoxic effects of xylodiol supports the hypothesis that the loss of ∆ψm is a late event in xylodiol-induced apoptosis.…”

Section: Discussionmentioning

confidence: 52%

Xylodiol from Xylopia langsdorfiana induces apoptosis in HL60 cells

Castello-Branco¹,

Tavares²,

Silva³

et al. 2011

Rev. bras. farmacogn.

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An atisane diterpene was isolated from Xylopia langsdorfi ana St. Hilaire & Tulasne, Annonaceae, leaves,. Preliminary study showed that xylodiol was cytotoxic and induced differentiation on human leukemia cell lines. However, the molecular mechanisms of xylodiol-mediated cytotoxicity have not been fully defined. Thus, we investigated the anti-tumor effect of xylodiol in human leukemia HL60 cell line. Xylodiol induced apoptosis and necrosis. HL60 cells treated with xylodiol showed biochemical changes characteristic of apoptosis, including caspases-8, -9 and -3 activation and loss of mitochondrial transmembrane potential (∆ψ m ). However, there was a condensation rather than swelling of mitochondria. Moreover, the formation of condensed mitochondria and the loss of ∆ψ m occurred downstream of caspase activation. Cyclosporine A did not protect HL60 cells from the cytotoxic effects of xylodiol, suggesting that the loss of ∆ψ m is a late event in xylodiol-induced apoptosis. Oxidative stress was involved in xylodiol-induced apoptosis. Thus, we conclude that activated caspases cleave cellular proteins resulting in mitochondrial damage leading to mitochondrial condensation, loss of ∆ψ m and ROS release from the mitochondria. ROS can further induce and maintain a collapse of ∆ψ m leading to cellular damage through oxidation of lipids and proteins resulting in apoptotic cell death.

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Section: Discussionmentioning

confidence: 52%

Xylodiol from Xylopia langsdorfiana induces apoptosis in HL60 cells

Castello-Branco¹,

Tavares²,

Silva³

et al. 2011

Rev. bras. farmacogn.

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“…This is evidence that CP-31398 restores mutant p53 to wild type, which then localizes to mitochondria where it disrupts permeability pores (34,61), which precedes the release of mitochondrial proteins to the cytosol. This was verified using cyclosporine A, a potent blocker of MPT (38). This compound blocked p53 mitochondrial translocation and inhibited CP-31398-mediated effects on apoptosis in these cells.…”

Section: Cp-31398 Reduces the Growth Of Uvb-induced Skin Tumors In Skmentioning

confidence: 99%

CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice

Tang

Zhu²,

Han³

et al. 2007

J. Clin. Invest.

115

100

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Mutations in the tumor suppressor p53 are detectable in over 50% of all human malignancies. Mutant p53 protein is incapable of transactivating its downstream target genes that are required for DNA repair and apoptosis. Chronic exposure to UVB induces p53 mutations and is carcinogenic in both murine and human skin. CP-31398, a styrylquinazoline compound, restores the tumor suppressor functions of mutant forms of p53 in tumor cells. However, its effectiveness in vivo remains unclear. Here, we demonstrate that CP-31398 blocked UVB-induced skin carcinogenesis and was associated with increases in p53, p21, and BclXs. CP-31398 downregulated Bcl2, proliferating nuclear cell antigen, and cyclin D1. Activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase also occurred in both tumor and perilesional skin following treatment. CP-31398 induced the expression of p53-dependent target proteins, and this was followed by apoptosis in UVB-irradiated wild-type mice but not in their p53-deficient littermates. Similar effects were observed in human skin carcinoma A431 cells expressing mutant p53. In addition, CP-31398 induced mitochondrial translocation of p53, leading to changes in mitochondrial membrane permeability pore transition (MPT) and consequent cytochrome c release in these cells. Blocking MPT diminished p53 translocation and apoptosis. These studies indicate that reconstituting p53 tumor suppressor functions in vivo by small molecular weight compounds may block the pathogenesis and progression of skin cancer.

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“…Protein modification by ubiquitin controls many cellular functions, and it does not always determine the degradation of the substrate. Monoubiquitination, polymonoubiquitination, and even polyubiquitination, when not involving the Lys 48 linkage, rather than promoting protein degradation, modulate protein activity in a signal-dependent manner (4).…”

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confidence: 99%

The Isopeptidase Inhibitor G5 Triggers a Caspase-independent Necrotic Death in Cells Resistant to Apoptosis

Fontanini

Foti

Potu

et al. 2009

Journal of Biological Chemistry

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Inhibitors of the ubiquitin-proteasome system (UPSIs) promote apoptosis of cancer cells and show encouraging anti-tumor activities in vivo. In this study, we evaluated the death activities of two different UPSIs: bortezomib and the isopeptidase inhibitor G5. To unveil whether these compounds elicit different types of death, we compared their effect both on apoptosis-proficient wild type mouse embryo fibroblasts and on cells defective for apoptosis (double-deficient Bax/Bak mouse embryo fibroblasts) (double knockout; DKO). We have discovered that (i) both inhibitors induce apoptosis in a Bax and Bak-dependent manner, (ii) both inhibitors elicit autophagy in WT and DKO cells, and (iii) only G5 can kill apoptosis-resistant DKO cells by activating a necrotic response. The induction of necrosis was confirmed by different experimental approaches, including time lapse analysis, HMGB1 release, and electron microscopy studies. Neither treatment with antinecrotic agents, such as antioxidants, poly(ADP-ribose) polymerase and JNK inhibitors, necrostatin, and the intracellular Ca 2؉ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid acetoxymethyl ester, nor overexpression of Bcl-2 and Bcl-xL prevented necrosis induced by G5. This necrotic death is characterized by the absence of protein oxidation and by the rapid cyclosporin A-independent dissipation of the mitochondrial membrane potential. Notably, a peculiar feature of the G5-induced necrosis is an early and dramatic reorganization of the actin cytoskeleton, coupled to an alteration of cell adhesion. The importance of cell adhesion impairment in the G5-induced necrotic death of DKO cells was confirmed by the antagonist effect of the extracellular matrixadhesive components, collagen and fibronectin.

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Cyclosporin A does not protect the disruption of the inner mitochondrial membrane potential induced by potassium ionophores in intact K562 cells

Cited by 15 publications

References 39 publications

Xylodiol from Xylopia langsdorfiana induces apoptosis in HL60 cells

Xylodiol from Xylopia langsdorfiana induces apoptosis in HL60 cells

CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice

The Isopeptidase Inhibitor G5 Triggers a Caspase-independent Necrotic Death in Cells Resistant to Apoptosis

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