Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis

Tsang, Wing Pui; Chau, Sophia P Y; Kong, Siu‐Kai; Fung, Kwok‐Pui; Kwok, Tsz-Ho

doi:10.1016/s0024-3205(03)00566-6

Cited by 247 publications

(175 citation statements)

References 23 publications

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“…Interestingly, ROS production in response to doxorubicin was significantly decreased by transient overexpression of Kir2.2. Taken together with previous reports that doxorubicin generates ROS (24,25), these results suggest that Kir2.2 likely blocks chemotherapeutic agent-induced senescence by inhibiting ROS generation.…”

Section: Ros Is a Critical Mediator Of Kir22 Knockdowninduced Senescsupporting

confidence: 86%

Knockdown of Inwardly Rectifying Potassium Channel Kir2.2 Suppresses Tumorigenesis by Inducing Reactive Oxygen Species–Mediated Cellular Senescence

Lee

Park²,

Kang³

2010

Molecular Cancer Therapeutics

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Senescence is an important determinant of treatment outcome in cancer therapy. In the present study, we show that knockdown of the inwardly rectifying K + channel Kir2.2 induced growth arrest without additional cellular stress in cancer cells lacking functional p53, p16, and/or Rb. Kir2.2 knockdown also induced senescence-associated β-galactosidase activity and upregulated senescence marker proteins in multiple cancer cell lines derived from different tissues, including prostate, stomach, and breast. Interestingly, knockdown of Kir2.2 induced a significant increase in reactive oxygen species (ROS) that was accompanied by cell cycle arrest, characterized by significant upregulation of p27, with concomitant downregulation of cyclinA, cdc2, and E2F1. Kir2.2 knockdown cells displayed increased levels of PML bodies, DNA damage (γH2AX) foci, senescence-associated heterochromatin foci, mitochondrial dysfunction, secretory phenotype, and phosphatase inactivation. Conversely, overexpression of Kir2.2 decreased doxorubicin-induced ROS accumulation and cell growth inhibition. Kir2.2 knockdown-induced cellular senescence was blocked by N-acetylcysteine, indicating that ROS is a critical mediator of this pathway. In vivo tumorigenesis analyses revealed that tumors derived from Kir2.2 knockdown cells were significantly smaller than those derived from control cells (P < 0.0001) and showed a remarkable increase in senescence-associated proteins, including senescence-associated β-galactosidase, p27, and plasminogen activator inhibitor-1. Moreover, the preestablished tumors are reduced in size after the injection of siKir2.2 (P = 0.0095). Therefore, we propose for the first time that Kir2.2 knockdown induces senescence of cancer cells by a mechanism involving ROS accumulation that requires p27, but not Rb, p53, or p16. Mol Cancer Ther; 9(11); 2951-9. ©2010 AACR.

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Section: Ros Is a Critical Mediator Of Kir22 Knockdowninduced Senescsupporting

confidence: 86%

Knockdown of Inwardly Rectifying Potassium Channel Kir2.2 Suppresses Tumorigenesis by Inducing Reactive Oxygen Species–Mediated Cellular Senescence

Lee

Park²,

Kang³

2010

Molecular Cancer Therapeutics

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“…[23][24][25] Therefore, we next investigated whether tetrandrine treatment could increase the ROS level in HCC cells. We measured intracellular ROS that was generated by the exposure of Huh7 and BEL7402 cells to 30 lM tetrandrine for different times.…”

Section: The Ros Is Involved In the Tetrandrine-induced Hcc Cell Apopmentioning

confidence: 99%

Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma

Liu¹,

Gong²,

Mao³

et al. 2011

Intl Journal of Cancer

129

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Tetrandrine, a bisbenzylisoquinoline alkaloid component of broadly used traditional Chinese medicine, has antitumor effects against some cancers. In our study, we investigated the effects of tetrandrine on the human hepatocellular carcinoma (HCC) in vitro and in vivo. The results showed that tetrandrine effectively induced apoptosis of liver cancer cell in a dose-and time-dependent manner accompanied by alteration of cell morphology, chromatin fragmentation and caspase activation. Tetrandrine treatment also induced intracellular accumulation of reactive oxygen species (ROS), and ROS scavengers (LNAC and GSH) completely blocked the effects of tetrandrine-induced apoptosis, suggesting that the generation of ROS plays an important role in tetrandrine-induced apoptosis. Although the activities of JNK and ERK were inhibited significantly by tetrandrine treatment, JNK and ERK are not involved in the tetrandrine-induced apoptosis. In contrast, Akt activity was found to be closely related to tetrandrine-induced apoptosis. The data demonstrated that Akt activity inhibitor LY294002 synergistically promoted tetrandrine-induced apoptosis of HCC, whereas ectopic expression of Akt contrastly abrogated partial of the tetrandrine-induced apoptosis. These data suggest that Akt signal is the downstream event of ROS generation in the tetrandrine-induced HCC cell apoptosis. Moreover, the results of xenograft in nude mice were consistent with that of the in vitro studies. Therefore, our data suggest that tetrandrine may be a promising agent for the treatment of HCC as a regulator of ROS/Akt pathway.

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“…This compound is then hydrolyzed by intracellular esterases to form DCFH, which in turn is oxidized by hydrogen peroxide to yield the high ly fluorescent compound 2'7' -dichlorofluorescein (DCF) [190]. Consistent with reports [163,197], after 6 hr of treatment WFA 1.5 IlM was significantly elevated over control cells from 2% to 17% (Fig. 25a-b).…”

Section: Ros-induced Cell Deathsupporting

confidence: 62%

Development of pituitary tumor-transforming gene (PTTG) transgenic mice for the treatment of ovarian cancer.

Fong¹

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Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis

Cited by 247 publications

References 23 publications

Knockdown of Inwardly Rectifying Potassium Channel Kir2.2 Suppresses Tumorigenesis by Inducing Reactive Oxygen Species–Mediated Cellular Senescence

Knockdown of Inwardly Rectifying Potassium Channel Kir2.2 Suppresses Tumorigenesis by Inducing Reactive Oxygen Species–Mediated Cellular Senescence

Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma

Development of pituitary tumor-transforming gene (PTTG) transgenic mice for the treatment of ovarian cancer.

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