p53-Defective Tumors With a Functional Apoptosome-Mediated Pathway: A New Therapeutic Target

Mashima, Tetsuo; Oh‐hara, Tomoko; Sato, Shigeo; Mochizuki, Mikiko; Sugimoto, Yoshikazu; Yamazaki, Kanami; Hamada, Jun Ichi; Tada, Mitsuhiro; Moriuchi, Tetsuya; Ishikawa, Yuichi; Kato, Yukio; Tomoda, Hiroshi; Yamori, Takao; Tsuruo, Takashi

doi:10.1093/jnci/dji133

Cited by 104 publications

(81 citation statements)

References 38 publications

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“…34 It was recently observed that tumor cells vary in terms of their apoptosome activity potential, and that inactivation of the apoptosome is a cause of chemoresistance and oncogenic transformation. 24,35,36 The Cell death and autophagy of Ph þ leukemias Y Kamitsuji et al expression of XIAP, and defective p53 molecules have been reported to inhibit the apoptosome. 24,37 It is believed that the natural cell death pathways are altered in apoptosomedefective cells.…”

Section: Discussionmentioning

confidence: 99%

“…24,35,36 The Cell death and autophagy of Ph þ leukemias Y Kamitsuji et al expression of XIAP, and defective p53 molecules have been reported to inhibit the apoptosome. 24,37 It is believed that the natural cell death pathways are altered in apoptosomedefective cells. Therefore, to overcome chemoresistance, it may be useful to develop agents that can trigger another cell death pathway, such as a caspase-independent pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, to overcome chemoresistance, it may be useful to develop agents that can trigger another cell death pathway, such as a caspase-independent pathway. 24 However, it remains unclear how the cell death patterns are altered in apoptosome-defective tumor cells. Here, we show for the first time that low-potential apoptosome activity in BcrAbl þ leukemic cells is associated with a predisposition to generate a CIA response to INNO-406, whereas a high potential apoptosome activity is associated with a tendency to produce a CIND response.…”

Section: Discussionmentioning

confidence: 99%

“…We examined 'the apoptosome activity potential', which is the intrinsic potential of the cells to activate caspase in a cyt c-induced apoptosome-mediated manner. 24 When the leukemic cell lines were tested for this parameter, we found that those that undergo CIND upon INNO-406 plus zVAD co-treatment tend to have a high apoptosome activity potential whereas those lines that undergo CIA tend to have a lower potential (Figure 3a). Expression levels of apoptosome components (apoptotic protease-activating factor-1; Apaf-1, cyt c and caspase-9) and caspase-3 proteins varied among the five cell lines, irrespective of apoptosome activity.…”

Section: Inno-406 Inducesmentioning

confidence: 99%

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The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

et al. 2008

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Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl þ ) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspaseindependent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl þ leukemias.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Inno-406 Inducesmentioning

confidence: 99%

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The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

et al. 2008

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“…The human MnSOD expression plasmid was a gift from Dr Abbadie at the Institute of Biology of Lille, France (Bernard et al, 2001). Dominant-negative mutants of human MEK1 (DN-MEK1; Wang et al, 2006) and caspase-9 (Mashima et al, 2005) were described elsewhere.…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

et al. 2008

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Chemoresistance and therapeutic selectivity are major obstacles to successful chemotherapy of ovarian cancer. Manganese superoxide disumutase (MnSOD) is an important antioxidant enzyme responsible for the elimination of superoxide radicals. We reported here that MnSOD was significantly elevated in ovarian cancer cells and its overexpression was one of the mechanisms that increased resistance to apoptosis in cancer cells. Knockdown of MnSOD by small-interfering RNA (siRNA) led to an increase in superoxide generation and sensitisation of ovarian cancer cells to the two front-line anti-cancer agents doxorubicin and paclitaxel whose action involved free-radical generation. This synergistic effect was not observed in non-transformed ovarian surface epithelial cells. Furthermore, our results revealed that this combination at the cellular level augmented activation of caspase-3 and caspase-9, but not caspase-8, suggesting involvement of an intrinsic apoptotic pathway. Evaluation of signalling pathways showed that MnSOD siRNA enhanced doxorubicin-and paclitaxel-induced phosphorylation of extracellular signal-regulated kinase 1/2. Akt activation was not affected. These results identify a novel chemoresistance mechanism in ovarian cancer, and show that combination of drugs capable of suppressing MnSOD with conventional chemotherapeutic agents may provide a novel strategy with a superior therapeutic index and advantage for the treatment of refractory ovarian cancer.

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Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non‐small cell lung cancer

et al. 2020

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Lung cancer is one of the most common cancers, still characterized by high mortality rates. As lipid metabolism contributes to cancer metabolic reprogramming, several lipid metabolism genes are considered prognostic biomarkers of cancer. Statins are a class of lipid-lowering compounds used in treatment of cardiovascular disease that are currently studied for their antitumor effects. However, their exact mechanism of action and specific conditions in which they should be administered remains unclear. Here, we found that simvastatin treatment effectively promoted antiproliferative effects and modulated lipid metabolism-related pathways in non-small cell lung cancer (NSCLC) cells and that the antiproliferative effects of statins were potentiated by overexpression of acyl-CoA synthetase long-chain family member 3 (ACSL3). Moreover, ACSL3 overexpression was associated with worse clinical outcome in patients with high-grade NSCLC. Finally, we found that patients with high expression levels of ACSL3 displayed a clinical benefit of statins treatment. Therefore, our study highlights ACSL3 as a prognostic biomarker for NSCLC, useful to select patients who would obtain a clinical benefit from statin administration.

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p53-Defective Tumors With a Functional Apoptosome-Mediated Pathway: A New Therapeutic Target

Abstract: Many p53-defective tumors retain activity of the apoptosome, which is therefore a potential target for cancer chemotherapy. Inhibition of ACS may be a novel strategy to induce the death of p53-defective tumor cells.

Cited by 104 publications

References 38 publications

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non‐small cell lung cancer

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