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Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

ABSTRACT: Curcumin and fenretinide are 2 well-known and promising chemotherapeutic compounds via various molecular mechanisms. However, the anticancer capacity of either curcumin or fenretinide is limited. This prompted us to examine the combined anticancer effects of curcumin and fenretinide. Our results demonstrate for the first time that there is synergistic anticancer effect of combined treatment with these 2 agents, leading to enhanced cytotoxicity and enhanced expression level of pro-apoptotic protein cleaved PARP in non-small cell lung cancer (NSCLC) cells while showed little toxicity to rat cardiomyoblast normal cells. The combination treatment was also demonstrated to inhibit lung carcinoma growth in vivo. Furthermore, we show that fenretinide or the ER stress inhibitor 4-PBA decreased curcumin-induced Glucose-regulated protein 78 (GRP78) upregulation, and produced a similar enhanced cytotoxic effect. In addition, GRP78 knockdown by siRNA also enhanced the cytotoxic effect of curcumin in A549 and H1299 cells. Our findings suggest that the 2 small molecules, when used in combination, can potentially be effective therapeutic agents for treating NSCLC, at least in part, by regulating endoplasmic reticulum (ER) chaperone protein GRP78.

SUBMITTER: Chen H

PROVIDER: S-EPMC5079384 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

Chen Huanxian H Chen Linmin L Wang Liang L Zhou Xinhua X Chan Judy Yuet-Wa JY Li Jingjing J Cui Guozhen G Lee Simon Ming-Yuen SM

Cancer biology & therapy 20160915 10

Curcumin and fenretinide are 2 well-known and promising chemotherapeutic compounds via various molecular mechanisms. However, the anticancer capacity of either curcumin or fenretinide is limited. This prompted us to examine the combined anticancer effects of curcumin and fenretinide. Our results demonstrate for the first time that there is synergistic anticancer effect of combined treatment with these 2 agents, leading to enhanced cytotoxicity and enhanced expression level of pro-apoptotic prote ...[more]

PMID: 27628049

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Project description:Epidermal growth factor receptor (EGFR) and c-MET receptors are expressed on many non-small cell lung cancer (NSCLC) cells. Current single agent therapeutic targeting of a mutant EGFR has a high efficacy in the clinic, but is not curative. Here, we investigated the combination of targeting EGFR and c-MET pathways in NSCLC cells resistant to receptor tyrosine kinase inhibitors (TKIs), using RNA interference and inhibition by TKIs. Different NSCLC cell lines with various genomic characteristics (H358, H1650 and H1975) were transfected with EGFR-specific-siRNA, T790M-specific-siRNA, c-MET siRNA or the combination. Subsequently EGFR TKIs (gefitinib, erlotinib or afatinib) or monoclonal antibody cetuximab were combined respectively with the c-MET-specific TKI su11274 in NSCLC cell lines. The cell proliferation, viability, caspase-3/7 activity and apoptotic morphology were monitored by spectrophotometry, fluorimetry and fluorescence microscopy. The combined effect of EGFR TKIs, or cetuximab and su11274, was evaluated using a combination index. The results showed that the cell lines that were relatively resistant to EGFR TKIs, especially the H1975 cell line containing the resistance T790M mutation, were found to be more sensitive to EGFR-specific-siRNA. The combination of EGFR siRNA plus c-MET siRNA enhanced cell growth inhibition, apoptosis induction and inhibition of downstream signaling in EGFR TKI resistant H358, H1650 and H1975 cells, despite the absence of activity of the c-MET siRNA alone. EGFR TKIs or cetuximab plus su11274 were also consistently superior to either agent alone. The strongest biological effect was observed when afatinib, an irreversible pan-HER blocker was combined with su11274, which achieved a synergistic effect in the T790M mutant H1975 cells. In a conclusion, our findings offer preclinical proof of principle for combined inhibition as a promising treatment strategy for NSCLC, especially for patients in whom current EGFR-targeted treatments fail due to the presence of the T790M-EGFR-mutation or high c-MET expression.

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Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

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Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer.

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