Enhancement of Cisplatin‐Induced Apoptosis and Caspase 3 Activation by Depletion of Mitochondrial DNA in a Human Osteosarcoma Cell Line

Yen, Hsiu-Chuan; Tang, Yi-Chia; Chen, Fan-Yi; Chen, Shih-Wei; Majima, Hideyuki J.

doi:10.1196/annals.1338.047

Cited by 23 publications

(15 citation statements)

References 14 publications

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“…The extent of apoptosis induced by treatment of TC-71 (42.4 F 0.1 %) and A4573 (41.7 F 2.3 %) cultures with roscovitine was markedly reduced when the treatment was carried out in the presence of Ac-DEVD-CHO (Table 1), which essentially prevented the apoptotic action of roscovitine and kept the proportions of apoptotic cells in the cultures at about background levels ( Table 1). The decrease in roscovitine-induced apoptotic levels caused by Ac-DEVD-CHO was consistent with the reduction in the apoptotic effect caused in the same cells by cisplatin (Table 1), a known inducer of caspase-dependent apoptosis in ESFT and other cell types (35,36), and with the extent of inhibition of the caspase-3/7 enzymatic activity induced by the inhibitor in TC-71 and A4573 cells (Fig. 4B).…”

Section: Resultssupporting

confidence: 65%

Roscovitine Is an Effective Inducer of Apoptosis of Ewing's Sarcoma Family Tumor CellsIn vitroandIn vivo

2005

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The Ewing's sarcoma family of tumors (ESFT) comprises several well-characterized malignant neoplasms with particularly aggressive behavior. Despite recent progress in the use of multimodal therapeutic approaches and aggressive local control measures, a substantial proportion of patients die because of disease progression. Furthermore, this outcome has not changed significantly over the last 15 to 20 years. Consequently, new, more effective therapeutic options are sorely needed for the treatment of ESFT. Because ESFT cells overexpress several cyclin-dependent kinases (CDK), we explored the efficacy against ESFT of roscovitine, a CDK inhibitor shown to be surprisingly safe for humans in clinical trials of their anticancer activity. Results showed that ESFT cell lines are uniformly sensitive to roscovitine. In addition to exerting comparatively minor cell cycle effects, roscovitine treatment concomitantly caused the up-regulation of the expression of the proapoptotic protein BAX and the downregulation of both survivin and XIAP, thus resulting in caspase-dependent apoptosis. Furthermore, in vivo experiments showed that s.c. growth of ESFT xenografts was also significantly slowed by i.p. injection of roscovitine. These results strongly suggest that roscovitine may be an effective therapeutic agent against ESFT and recommend its evaluation against ESFT in clinical trials and its inclusion in future treatment protocols. (Cancer Res 2005; 65(20): 9320-27)

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Section: Resultssupporting

confidence: 65%

Roscovitine Is an Effective Inducer of Apoptosis of Ewing's Sarcoma Family Tumor CellsIn vitroandIn vivo

2005

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“…This effect was cisplatin dose-dependent (data not shown). Increased mitochondrial O 2 .-formation has been associated with the release of cytochrome c and apoptosis (2,8), yet cisplatin (20 μM, 24-and 48-h treatment) induced an increase of mitochondrial O 2 .-in A549 cells as shown using flow cytometry and the dye MitoSOX ( Fig. 2B and C).…”

Section: Cisplatin Disrupts the Steady-state Level Of Mitochondrial Rmentioning

confidence: 99%

“…Cisplatin forms DNA adducts, yet its ability to induce programmed cell death (apoptosis) in both cancer and normal cells has been associated with the formation of reactive oxygen species (ROS) in the mitochondria, cytochrome c release into the cytosol, and subsequent activation of caspases (2)(3)(4)(5)(6)(7)(8). One report suggests that cytochrome c release is required for cisplatin-induced apoptosis, yet a caspase 3-independent pathway has been reported as well (8,9).…”

Section: Introductionmentioning

confidence: 99%

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

Kachadourian

Leitner²,

Day³

2007

Int J Oncol

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Abstract. Adjuvant therapies that enhance the anti-tumor effects of cis-diammineplatinum(II) dichloride (cisplatin, CDDP) are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cisplatin. We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glutathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 μM, 48-h treatment) disrupts the steady-state levels of mitochondrial respiratory complex I, which correlates with elevated mitochondrial reactive oxygen species (ROS) production and cytochrome c release. The flavonoids, 2',5'-dihydroxychalcone (2',5'-DHC, 20 μM) and chrysin (20 μM) potentiated the cytotoxicity of cisplatin (20 μM), which could be blocked by supplementation of the media with exogenous GSH (500 μM). Both 2',5'-DHC and chrysin were more effective than the specific inhibitor of GSH synthesis, L-buthionine sulfoximine (BSO, 20 μM), in inducing GSH depletion and potentiating the cytotoxic effect of cisplatin. These data suggest that the flavonoid-induced potentiation of cisplatin's toxicity is due, in part, to synergetic pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and the flavonoids by depleting cellular GSH, an important antioxidant defense.

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“…It is known that both mtDNA single-strand breaks [119] as well as complete loss of mtDNA [120] predispose cells to apoptosis, further indicating that mtDNA and its integrity have central roles in cell fate determination.…”

Section: A Role For Mtdna In Cardiac Protection and Ageingmentioning

confidence: 99%

The role of mitochondria in cardiac development and protection

Pohjoismäki

Goffart

2017

Free Radical Biology and Medicine

107

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Mitochondria are essential for the development as well as maintenance of the myocardium, the most energy consuming tissue in the human body. Mitochondria are not only a source of ATP energy but also generators of reactive oxygen species (ROS), that cause oxidative damage, but also regulate physiological processes such as the switch from hyperplastic to hypertrophic growth after birth. As excess ROS production and oxidative damage are associated with cardiac pathology, it is not surprising that much of the research focused on the deleterious aspects of free radicals. However, cardiomyocytes are naturally highly adapted against repeating oxidative insults, with evidence suggesting that moderate and acute ROS exposure has beneficial consequences for mitochondrial maintenance and cardiac health. Antioxidant defenses, mitochondrial quality control, mtDNA maintenance mechanisms as well as mitochondrial fusion and fission improve mitochondrial function and cardiomyocyte survival under stress conditions. As these adaptive processes can be induced, promoting mitohormesis or mitochondrial biogenesis using controlled ROS exposure could provide a promising strategy to increase cardiomyocyte survival and prevent pathological remodeling of the myocardium.

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Enhancement of Cisplatin‐Induced Apoptosis and Caspase 3 Activation by Depletion of Mitochondrial DNA in a Human Osteosarcoma Cell Line

Cited by 23 publications

References 14 publications

Roscovitine Is an Effective Inducer of Apoptosis of Ewing's Sarcoma Family Tumor CellsIn vitroandIn vivo

Roscovitine Is an Effective Inducer of Apoptosis of Ewing's Sarcoma Family Tumor CellsIn vitroandIn vivo

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

The role of mitochondria in cardiac development and protection

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