Retinoids in combination therapies for the treatment of cancer: mechanisms and perspectives

Ortiz, María A.; Bayón, Yolanda; López-Hernández, Francisco J.; Piedrafita, F. Javier

doi:10.1016/s1368-7646(02)00050-x

Cited by 42 publications

(34 citation statements)

References 85 publications

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“…8,9 The discovery of GRIM-19 as an IFN-b/RA-inducible gene product 10 role of MRC in cell death seems specific only for the combination of IFN-b and RA, as IFN or RA alone did not induce either upregulation of the MRC subunits or the cell death (Figures 1 and 2). Furthermore, other death stimuli such as UV, CPT, and staurosporine caused cell death without inducing the expression of GRIM-19 and NDUFS3, and knockdown of these two genes did not prevent cell death induced by these generic death agents (Supplementary Figure 2).…”

Section: Discussionmentioning

confidence: 99%

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Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Huang

Chen

et al. 2006

Cell Death Differ

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Combination of retinoic acids (RAs) and interferons (IFNs) has synergistic apoptotic effects and is used in cancer treatment. However, the underlying mechanisms remain unknown. Here, we demonstrate that mitochondrial respiratory chain (MRC) plays an essential role in the IFN-b/RA-induced cancer cell death. We found that IFN-b/RA upregulates the expression of MRC complex subunits. Mitochondrial-nuclear translocation of these subunits was not observed, but overproduction of reactive oxygen species (ROS), which causes loss of mitochondrial function, was detected upon IFN-b/RA treatment. Knockdown of GRIM-19 (gene associated with retinoid-interferon-induced mortality-19) and NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-b/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-b/RA that are directly involved in growth inhibition and cell death was also repressed in the knockdown cells. Our data suggest that the MRC regulates IFN-b/RA-induced cell death by modulating ROS production and late gene expression.

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Section: Discussionmentioning

confidence: 99%

“…Various combinations of RAs and IFNs have demonstrated synergistic effects by inhibiting proliferation and inducing differentiation, as well as apoptotic activity in cancer cell lines and in human hematologic and solid tumor models. 8,9 However, the molecular basis of their effects is poorly understood.…”

mentioning

confidence: 99%

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Huang

Chen

et al. 2006

Cell Death Differ

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“…Retinoids are important potential cancer therapy and prevention agents (Altucci and Gronemeyer, 2001;Fontana and Rishi, 2002;Hammond et al, 2002;Ortiz et al, 2002;Sun and Lotan, 2002). Retinoids are a class of natural and synthetic vitamin A analogs that regulate a range of biological processes including cell growth, cell differentiation and apoptosis (Petkovich et al, 1987;Brand et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…These agents promote apoptosis in a variety of tumor cell types and frequently display reduced toxicity compared to classical retinoids. Fenretinide induces apoptosis of prostate and ovarian cells and prevents oral leukoplakia (Chiesa et al, 1992;Pienta et al, 1993;Supino et al, 1996;Hsieh and Wu, 1997;Ortiz et al, 2002). CD437 induces receptor-independent apoptosis in lung, cervical, breast and ovarian cancer cells (Shao et al, 1995;Hsu et al, 1997;Oridate et al, 1997;Sun et al, 1997;Holmes et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

2005

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acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)-or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR-or RXR receptorselective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclindependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.

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“…Novel synthetic retinoid-related molecules (RRMs) that are selective agonists for RARg (CD437, MX2870-1, and MX3350-1) as well as one RRM antagonist (MX781) have been found to exhibit strong antiproliferative and apoptotic-inducing activities against numerous cancer cell lines in vitro [28][29][30][31][32] and in vivo 33,34 Thus, they show promise as lead compounds for the treatment of cancer as single-drug therapy or in combination with other anticancer agents. 35 These compounds are suspected to exert their apoptotic activity through a novel mechanism of retinoid action, which is independent of the nuclear receptors. 32,36 CD437 has been suggested to induce apoptosis by directly targeting mitochondria, 37 although nuclear export of the orphan receptor nur77 and relocation to the mitochondria has also been indicated to mediate CD437-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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Certain retinoid-related molecules (RRMs) with agonist or antagonist activities have been described to induce apoptosis in a variety of cancer cell lines and show promise for the treatment of cancer. Similar to other chemotherapeutic drugs, these retinoid analogs have been suggested to induce apoptosis through the intrinsic pathway, which requires the release of cytochrome c from the mitochondria for the effective activation of caspase 9. Expression of a catalytically inactive form of caspase 9, which functions as a dominant negative mutant, inhibits the induction of DEVDase activity and nuclear fragmentation by selective RRMs. Whereas the RRMs could induce the release of cytochrome c in the absence of caspase 9 activity, the later is necessary for the effective release of Smac/Diablo from the mitochondria. Furthermore, overexpression of Bcl-2 or Bcl-X L also inhibits RRM-induced apoptosis. We demonstrate that activation of caspase 2 by the agonist MX2870-1 requires caspase 9 activity and is inhibited by Bcl-2 overexpression. In contrast, the antagonist MX781 induces cleavage of procaspase 2 upstream of mitochondria and independently of caspase 9. Thus, two retinoid analogs with unique characteristics activate two distinct apical caspases (2 or 9) to initiate apoptosis. In addition to caspase-mediated cell death, sustained exposure to the RRMs can also lead to loss of cell viability in cells lacking caspase 9 activity or in cells stimulated in the presence of the caspase inhibitor Z-VADfmk. Moreover, MX2870-1 and MX781 produce cell cycle arrest independently of caspase activity and the retinoid receptors.

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Retinoids in combination therapies for the treatment of cancer: mechanisms and perspectives

Cited by 42 publications

References 85 publications

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

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