Fenretinide: A p53-independent way to kill cancer cells

Corazzari, Marco; Lovat, Penny E.; Oliverio, Serafina; Sano, Federica Di; Donnorso, R. Perrone; Redfern, Christopher P.F.; Piacentini, Mauro

doi:10.1016/j.bbrc.2005.03.184

Cited by 46 publications

(39 citation statements)

References 47 publications

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“…Recent paper reported that GADD153 is an important transcription factor for 4HPR-induced apoptosis in a p53-independent manner, and that this is mediated through activation of 12-lipoxygenase leading to endoplasmic reticulum (ER) stress. 36 Interestingly, 4HPR acts synergistically with chemotherapeutic drugs similar to EGCG. Whether the combinations with EGCG plus celecoxib, sulindac or ATRA induce ER stress in lung cancer cells needs to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene

Suganuma

Kurusu

Suzuki

et al. 2006

Intl Journal of Cancer

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To more clearly understand the molecular mechanisms involved in synergistic enhancement of cancer preventive activity with the green tea polyphenol (2)-epigallocatechin gallate (EGCG), we examined the effects of cotreatment with EGCG plus celecoxib, a cyclooxygenase-2 selective inhibitor. We specifically looked for induction of apoptosis and expression of apoptosis related genes, with emphasis on growth arrest and DNA damage-inducible 153 (GADD153) gene, in human lung cancer cell line PC-9: Cotreatment with EGCG plus celecoxib strongly induced the expression of both GADD153 mRNA level and protein in PC-9 cells, while neither EGCG nor celecoxib alone did. However, cotreatment did not induce expression of other apoptosis related genes, p21 WAF1 and GADD45. Judging by upregulation of GADD153, only cotreatment with EGCG plus celecoxib synergistically induced apoptosis of PC-9 cells. Synergistic effects with the combination were also observed in 2 other lung cancer cell lines, A549 and ChaGo K-1. Furthermore, EGCG did not enhance GADD153 gene expression or apoptosis induction in PC-9 cells in combination with N-(4-hydroxyphenyl)retinamide or with aspirin. Thus, upregulation of GADD153 is closely correlated with synergistic enhancement of apoptosis with EGCG. Cotreatment also activated the mitogen-activated protein kinases (MAPKs), such as ERK1/2 and p38 MAPK: Preteatment with PD98059 (ERK1/2 inhibitor) and UO126 (selective MEK inhibitor) abrogated both upregulation of GADD153 and synergistic induction of apoptosis of PC-9 cells, while SB203580 (p38 MAPK inhibitor) did not do so, indicating that GADD153 expression was mediated through the ERK signaling pathway. These findings indicate that high upregulation of GADD153 is a key requirement for cancer prevention in combination with EGCG. ' 2006 Wiley-Liss, Inc.Key words: EGCG; apoptosis; ERK1/2; prevention (2)-Epigallocatechin gallate (EGCG), a main constituent of green tea polyphenol, can act synergistically with cancer preventive agents (such as sulindac and tamoxifen) in inducing apoptosis of lung, colon and breast cancer cells. 1-3 Since EGCG and green tea have a wide range of target organs and are nontoxic for animals and humans, there is growing interest in increasing the antitumor activity of cancer preventive agents in combination with EGCG or green tea. [4][5][6] However, the molecular mechanisms responsible for the synergistic effects of cotreatment with EGCG plus cancer preventive agents are not known. Using human cDNA cancer expression array, we have found upregulated expressions of 2 genes, growth arrest and DNA damage-inducible gene 153 (GADD153) and p21 WAF1 , and downregulated expressions of 4 genes, T-plasminogen activator, TIMP3, IL-1b and integrin b4: All of these genes are associated with synergistic induction of apoptosis of human non-small-cell lung carcinoma (NSCLC) cell line PC-9 by cotreatment with EGCG plus sulindac. 7 Treatment with either EGCG or sulindac alone did not affect these gene expressions. Since upregulation of GADD153 gene expressi...

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Section: Discussionmentioning

confidence: 99%

Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene

Suganuma

Kurusu

Suzuki

et al. 2006

Intl Journal of Cancer

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“…Studies aimed at determining the precise mechanism of 4-HPR-induced apoptosis suggest that this takes place through a wide range of mechanisms, many of which are not mutually exclusive. These include a p53-independent pathway involving elevation of intracellular ceramide levels (21), increases in intracellular reactive oxygen species (22), activation of members of the activator protein-1 (AP-1) transcription factor family (23), and activation of caspase 8 (24).…”

Section: Fenretinide [N -(4-hydroxyphenyl)retinamide or 4-hpr]mentioning

confidence: 99%

Chemoprevention of Skin Carcinogenesis by Phenylretinamides: Retinoid Receptor–Independent Tumor Suppression

Xu¹,

Cheepala

McCauley

et al. 2006

Clinical Cancer Research

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Fenretinide [N-(4-hydroxyphenyl)retinamide or 4-HPR] is a synthetic retinoid analogue with antitumor and chemopreventive activities. N-(4-Methoxyphenyl)retinamide (4-MPR) is the most abundant metabolite of 4-HPR detected in human serum following 4-HPR therapy. We have shown in in vitro studies that 4-HPR and 4-MPR can act independent of the classic nuclear retinoid receptor pathway and that 4-HPR, but not 4-MPR, can also activate nuclear retinoid receptors. In this study, we have compared the chemopreventive effects of topically applied 4-HPR and 4-MPR with the primary biologically active retinoid, all-trans retinoic acid (ATRA), in vivo in the mouse skin two-stage chemical carcinogenesis model. All three retinoids suppressed tumor formation but the effect of 4-HPR and 4-MPR, and not of ATRA, was sustained after their discontinuation. The tumor-suppressive effects of 4-HPR and 4-MPR were quantitatively and qualitatively similar, suggesting that the two may be acting through the same retinoid receptorî ndependent mechanism(s). We further explored this effect in vitro by analyzing primary cultures of mouse keratinocytes treated with the same retinoids. All three could induce apoptosis with a 48-hour treatment and onlyATRA and 4-HPR induced an accumulation of cells in the G 1 phase of the cell cycle. This finding is consistent with our previous results showing that the effects of phenylretinamides on the cell cycle are retinoid receptor dependent whereas apoptosis induction is not. A microarray-based comparison of gene expression profiles for mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) alone and TPA + 4-HPR orTPA + 4-MPR reveals a high degree of coincidence between the genes regulated by the two phenylretinamides.We propose that 4-HPR may exert therapeutic and chemopreventive effects by acting primarily through a retinoid receptor^independent mechanism(s) and that 4-MPR may contribute to the therapeutic effect of 4-HPR by acting through the same retinoid receptor^independent mechanism(s).

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“…In addition, the synthetic retinoid fenretinide induces p53-indepenent apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs. The upstream signaling events induced by fenretinide include an increase in the intracellular levels of ceramide, which eventually lead to oxidative stress and apoptosis (30).…”

Section: Discussionmentioning

confidence: 99%

A New Isoquinolinium Derivative, Cadein1, Preferentially Induces Apoptosis in p53-defective Cancer Cells with Functional Mismatch Repair via a p38-dependent Pathway

Jang

Ryu

Park

et al. 2010

Journal of Biological Chemistry

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We screened a protoberberine backbone derivative library for compounds with anti-proliferative effects on p53-defective cancer cells. A compound identified from this small molecule library, cadein1 (cancer-selective death inducer 1), an isoquinolinium derivative, effectively leads to a G 2 /M delay and caspasedependent apoptosis in various carcinoma cells with nonfunctional p53. The ability of cadein1 to induce apoptosis in p53-defective colon cancer cells was tightly linked to the presence of a functional DNA mismatch repair (MMR) system, which is an important determinant in chemosensitivity. Cadein1 was very effective in MMR ؉ /p53 ؊ cells, whereas it was not effective in p53 ؉ cells regardless of the MMR status. Consistently, when the function of MMR was blocked with short hairpin RNA in SW620 (MMR ؉ /p53 ؊ ) cells, cadein1 was no longer effective in inducing apoptosis. Besides, the inhibition of p53 increased the pro-apoptotic effect of cadein1 in HEK293 (MMR ؉ /p53 ؉ ) cells, whereas it did not affect the response to cadein1 in RKO (MMR ؊ /p53 ؉ ) cells. The apoptotic effects of cadein1 depended on the activation of p38 but not on the activation of Chk2 or other stressactivated kinases in p53-defective cells. Taken together, our results show that cadein1 may have a potential to be an anticancer chemotherapeutic agent that is preferentially effective on p53-mutant colon cancer cells with functional MMR.

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Fenretinide: A p53-independent way to kill cancer cells

Cited by 46 publications

References 47 publications

Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene

Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene

Chemoprevention of Skin Carcinogenesis by Phenylretinamides: Retinoid Receptor–Independent Tumor Suppression

A New Isoquinolinium Derivative, Cadein1, Preferentially Induces Apoptosis in p53-defective Cancer Cells with Functional Mismatch Repair via a p38-dependent Pathway

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