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Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.

ABSTRACT: Here, we showed the antibiotic salinomycin (SAL) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status, with a relatively low toxicity to normal cells. Additionally, combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF. Further, we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP) and lysosomal membrane potential (LMP). And the ROS contributed the loss of MMP and LMP. We also found that GEF and SAL acted in concert to induce apoptosis via a mitochondrial-lysosomal cross-talk and caspase-independent pathway triggered by cathepsin B and D. Lastly, SAL in combination with GEF sensitized GEF-resistant cells to GEF in a nude mouse xenograft model. This novel combination treatment might provide a potential clinical application to overcome GEF resistance in colorectal cancer.

SUBMITTER: Zou ZZ

PROVIDER: S-EPMC5410233 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.

Zou Zheng-Zhi ZZ Nie Pei-Pei PP Li Ya-Wei YW Hou Ben-Xin BX Rui-Li Shi Xin-Peng XP Ma Zhao-Kui ZK Han Bao-Wei BW Luo Xiao-Yong XY

Oncotarget 20170401 14

Here, we showed the antibiotic salinomycin (SAL) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status, with a relatively low toxicity to normal cells. Additionally, combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF. Further, we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxyg ...[more]

PMID: 26461472

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Project description:Background:Our previous clinical study has shown that Chinese herbal medicine (CHM) Fuzheng Kang-Ai (FZKA) decoction is effective in treating advanced lung cancer patients through prolonging the drug resistance to Gefitinib (GFTN). Our basic study found that FZKA decoction could enhance the inhibition effect of GFTN in lung cancer by inactivating PI3K/Akt pathway. Moreover, our recent work showed that FZKA induced lung cancer cell apoptosis via STAT3/Bcl-2/Caspase-3 pathway. Thus in this study, we aim to elucidate how FZKA enhances the effect of GFTN in lung cancer from the perspective of cell apoptosis. Methods:Cell proliferation and colony formation assay were performed to detect the cell growth inhibition. Flow cytometry and TUNEL assay were carried out to test the cell apoptosis. Mitochondrial membrane potential (MMP) assay was done to measure the alteration of MMP. Caspase-3/-9 activity assay was used to test the activity of caspase-3/-9. Western blot and qRT-PCR were done to detect the expression of STAT3 and Bcl-2 family as well as Caspase-3/-9 and Cyt-C at protein and mRNA levels, respectively. Transient transfection was performed to silence STAT3 using siSTAT3. Animal model was done to validate the molecular mechanisms in vivo and immunohistochemistry was done to detect the expression of Bax and Caspase-3. Results:Firstly, our results showed that FZKA enhanced the inhibition effect of GFTN in lung cancer both in vitro and in vivo. Secondly, cell apoptosis was enhanced when treating lung cancer cells with both FZKA and GFTN, a process involving the mitochondria and the Bcl-2 family. And Bcl-2 family was involved in this process. Interestingly, STAT3 plays a critical role on mediating the above process. Last but not the least, the enhanced effect of cell apoptosis induction of GFTN by FZKA was validated in animal model. Conclusion:Our findings conclude that Fuzheng Kang-Ai decoction enhances the effect of GFTN-induced cell apoptosis in lung cancer through the mitochondrial pathway, providing a novel molecular mechanism by which FZKA sensitizes to GFTN by delaying drug resistance in treating lung cancer patients.

Project description:BackgroundTumors are heterogeneous in nature, composed of different cell populations with various mutations and/or phenotypes. Using a single drug to encounter cancer progression is generally ineffective. To improve the treatment outcome, multiple drugs of distinctive mechanisms but complementary anticancer activities (combination therapy) are often used to enhance antitumor efficacy and minimize the risk of acquiring drug resistance. We report here the synergistic effects of salinomycin (a polyether antibiotic) and dasatinib (a Src kinase inhibitor).MethodsFunctionally, both drugs induce cell cycle arrest, intracellular reactive oxygen species (iROS) production, and apoptosis. We rationalized that an overlapping of the drug activities should offer an enhanced anticancer effect, either through vertical inhibition of the Src-STAT3 axis or horizontal suppression of multiple pathways. We determined the toxicity induced by the drug combination and studied the kinetics of iROS production by fluorescence imaging and flow cytometry. Using genomic and proteomic techniques, including RNA-sequencing (RNA-seq), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western Blot, we subsequently identified the responsible pathways that contributed to the synergistic effects of the drug combination.ResultsCompared to either drug alone, the drug combination showed enhanced potency against MDA-MB-468, MDA-MB-231, and MCF-7 human breast cancer (BC) cell lines and tumor spheroids. The drug combination induces both iROS generation and apoptosis in a time-dependent manner, following a 2-step kinetic profile. RNA-seq data revealed that the drug combination exhibited synergism through horizontal suppression of multiple pathways, possibly through a promotion of cell cycle arrest at the G1/S phase via the estrogen-mediated S-phase entry pathway, and partially via the BRCA1 and DNA damage response pathway.ConclusionTranscriptomic analyses revealed for the first time, that the estrogen-mediated S-phase entry pathway partially contributed to the synergistic effect of the drug combination. More importantly, our studies led to the discoveries of new potential therapeutic targets, such as E2F2, as well as a novel drug-induced targeting of estrogen receptor β (ESR2) approach for triple-negative breast cancer treatment, currently lacking of targeted therapies.

Dataset Information

Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.

Publications

Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.

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