The Mitochondrial Death Pathway

Chalah, Anas; Khosravi‐Far, Roya

doi:10.1007/978-1-4020-6554-5_3

Cited by 93 publications

(64 citation statements)

References 145 publications

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“…3B). Also the analysis of cytochrome c release, a reliable indicator of apoptosis, 19 did not show any evidence of the apoptotic process (Fig. 3C).…”

Section: Resultsmentioning

confidence: 89%

The plant alkaloid voacamine induces apoptosis-independent autophagic cell death on both sensitive and multidrug resistant human osteosarcoma cells

Meschini¹,

Condello²,

Calcabrini³

et al. 2008

Autophagy

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In our previous studies, the bisindolic alkaloid voacamine (VOA), isolated from the plant Peschiera fuchsiaefolia, proved to exert a chemosensitizing effect on cultured multidrug resistant (MDR) osteosarcoma cells exposed to doxorubicin (DOX). In particular, VOA was capable of inhibiting P-glycoprotein action in a competitive way, thus explaining the enhancement of the cytotoxic effect induced by DOX on MDR cells. Afterwards, preliminary observations suggested that such an enhancement did not involve the apoptotic process but was due instead to the induction of autophagic cell death. The results of the present investigation demonstrate that the plant alkaloid VOA is an autophagy inducer able to exert apoptosis-independent cytotoxic effect on both wild-type and MDR tumor cells. In fact, under treatment condition causing about 50 percent of cell death, no evidence of apoptosis could be revealed by microscopical observations, Annexin V-FITC labeling and analysis of PARP cleavage, whereas the same cells underwent apoptosis when treated with apoptosis inducers, such as doxorubicin and staurosporine. Conversely, VOA-induced autophagy was clearly evidentiated by electron microscopy observations, monodansylcadaverine staining, LC3 expression, and conversion. These results were confirmed by the analysis of the modulating effects of the pretreatment with autophagy inhibitors prior to VOA administration. In addition, transfection of osteosarcoma cells with siRNA against ATG genes reduced VOA cytotoxicity. In conclusion, considering the very debated dual role of autophagy in cancer cells (protective or lethal, pro-or anti-apoptotic) our findings seem to demonstrate, at least in vitro, that a natural product able to induce autophagy can be effective against drug resistant tumors, either used alone or in association with conventional chemotherapeutics.

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“…3B). Also the analysis of cytochrome c release, a reliable indicator of apoptosis, 19 did not show any evidence of the apoptotic process (Fig. 3C).…”

Section: Resultsmentioning

confidence: 89%

The plant alkaloid voacamine induces apoptosis-independent autophagic cell death on both sensitive and multidrug resistant human osteosarcoma cells

Meschini¹,

Condello²,

Calcabrini³

et al. 2008

Autophagy

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“…Menurunnya ekspresi caspase-3 dapat merefleksikan penurunan apoptosis sel. 13 Ekspresi protein Bcl-2 meningkat seiring dengan makin seringnya paparan hipoksia hipobarik, sebaliknya ekspresi caspase-3 cenderung menurun, hal ini juga dipengaruhi oleh gen yang sangat sensitif terhadap hipoksia, yaitu HIF-1α (Tabel 1). Ternyata pada keadaan hipoksia, gen HIF-1α akan stabil dan tidak didegradasi.…”

Section: -11unclassified

Ekspresi Bcl-2 dan Caspase-3 Pascapaparan Hipoksia Hipobarik Intermiten

Hidayat¹,

Hernowo²,

Hanggono³

et al. 2011

mkb

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AbstrakHipoksia hipobarik intermiten sering dialami oleh awak pesawat, karena selama di dalam kabin pesawat bernapas dengan tekanan udara yang lebih rendah. Tubuh akan beradaptasi dengan cara mengikat oksigen lebih banyak dan juga mengurangi dampak hipoksia. Fungsi mitokondria akan terganggu pada hipoksia, yaitu permiabilitas membran luar mitokondria karena protein Bcl-2 menurun. Jika hipoksia berlanjut akan terjadi kebocoran membran mitokondria, pelepasan sitokrom-c, dan proses apoptosis berlangsung. Penelitian ini bertujuan menganalisis protein Bcl-2 sebagai antiapoptosis dan caspase-3 sebagai indikator apoptosis akibat paparan hipoksia hipobarik intermiten. Dilakukan penelitian eksperimental pada tikus jantan Spraque Dawley periode Januari-April 2010 dengan melakukan paparan hipoksia hipobarik intermiten satu sampai empat kali dengan interval satu minggu. Jantung tikus dijadikan spesimen untuk dilakukan pemeriksaan ekspresi protein dengan pulasan imunohistokimia di Departemen Patologi Anatomi RS Dr. Hasan Sadikin Bandung dan western blot di Bagian Biomolekuler FK Universitas Indonesia Jakarta. Ekspresi protein Bcl-2 meningkat sesuai dengan frekuensi paparan hipoksia hipobarik intermiten, sebaliknya ekspresi protein caspase-3 menurun (r s =-0,448, p=0,013). Dari penelitian ini dapat disimpulkan bahwa terjadi penurunan tingkat apoptosis akibat paparan hipoksia hipobarik intermiten, hal ini disebabkan mekanisme adaptasi natural yang ditandai dengan menurunnya apoptosis sel dan secara tidak langsung akan memberi efek kardioprotektif. [MKB. 2011;43(4):166-70].Kata kunci: Apoptosis, Bcl-2, caspase-3, hipoksia hipobarik intermiten Bcl-2 and Caspase-3 Expression Post Exposure of Intermittent Hypobaric Hypoxia AbstractIntermittent hypobaric hypoxia often suffered by cabin crew due to the fact that they are breathing lower pressured air inside the plane cabin. Human body will adapt by binding more oxygen and reducing hypoxia effect. Mitochondria function will be irritated by hypoxia which affect, outer mithochondrial membrane permeability due to decrease of Bcl-2 protein. Later on if hypoxia continues mitochondrial membrane will leaked cytocrome-c will released and apoptotic pathway will occur. The purpose of this study was to analyze Bcl-2 protein as antiapoptosis and caspase-3 as apoptosis indicator of intermittent hypobaric hypoxia exposure. Experimental study was subjected to Spraque Dawley male mice during January-April 2010 by exposing them to several intermittent hypobaric hypoxias (one to four treatment) in an interval of one week. Protein expression on mice heart cell were detected by immunohistochemistry in the Department of Pathology Anatomy Padjadjaran University-RS Dr. Hasan Sadikin Bandung and western blot methods in Department Biomolecullar Indonesia University Jakarta. Bcl-2 protein expressions increased according with the frequency of intermittent hypobaric hypoxia exposures, while a reverse trend was found for caspase-3 protein expressions (r s =-0.448, p=0.013). From the study it can be concluded tha...

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“…Key factors regulating Δae include calcium, cellular redox status (including levels of reactive oxygen species) and the mobilization and targeting of mitochondria Bcl-2 family members. Hence, activating the collapse of Δae would be an important step in initiating apoptosis in glioma cells (5,6).…”

Section: Introductionmentioning

confidence: 99%

RNAi-mediated downregulation of MMP-2 activates the extrinsic apoptotic pathway in human glioma xenograft cells

Gondi

Talluri

Dinh³

et al. 2009

Int J Oncol

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Abstract. Malignant gliomas are characterized by invasive and infiltrative behavior that generally involves the destruction of normal brain tissue. Strategies to treat infiltrating gliomas, such as chemotherapy and gene therapy, have remained largely unsuccessful. The infiltrative nature of gliomas can be attributed largely to proteases, which include serine, metallo-and cysteine-proteases. Our previous work and that of others strongly suggest a relationship between the expression of uPAR, MMP-9, and MMP-2; this relationship is generally indicative of the infiltrative phenotype of gliomas. In the present study, we have demonstrated that the RNAi-mediated downregulation of MMP-2 induces apoptosis in the 4910 human glioma xenograft cell line. Using Western blot analysis, we observed that caspase-8 levels increased in MMP-2-downregulated cells whereas TRADD and TRAF-2 levels decreased. Further, NIK levels increased in MMP-2-downregulated cells. To determine the nuclear localization of AIF and IκB·, we analyzed the levels of AIF, IκB· and pIκB· in the cytosolic and nuclear fractions of MMP-2-downregulated cells. Western blot analysis revealed that MMP-2 downregulation resulted in the translocation of AIF to the nucleus and also inhibited the nuclear localization of pIκB·. To confirm the involvement of AIF, we performed FACS analysis to determine the integrity of the mitochondrial membrane using the MitoPT method. FACS analysis showed that the downregulation of MMP-2 caused a collapse in the mitochondrial cell membrane. Immunolocalization of AIF revealed that in MMP-2-downregulated cells, AIF translocates to the nucleus, thereby enabling the induction of apoptosis. RT-PCR analysis revealed that caspase-8 was overexpressed 57-fold, whereas p73 was downregulated 28-fold. Evidence of apoptosis was determined by TUNEL assay and visualization of nuclear fragmentation by DAPI staining. In summary, it is evident from our results that MMP-2 downregulation induces caspase-8 and AIF-mediated apoptosis and, as such, shows potential for glioma therapy.

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The Mitochondrial Death Pathway

Cited by 93 publications

References 145 publications

The plant alkaloid voacamine induces apoptosis-independent autophagic cell death on both sensitive and multidrug resistant human osteosarcoma cells

The plant alkaloid voacamine induces apoptosis-independent autophagic cell death on both sensitive and multidrug resistant human osteosarcoma cells

Ekspresi Bcl-2 dan Caspase-3 Pascapaparan Hipoksia Hipobarik Intermiten

RNAi-mediated downregulation of MMP-2 activates the extrinsic apoptotic pathway in human glioma xenograft cells

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