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The anticancer effect of chaetocin is enhanced by inhibition of autophagy.

ABSTRACT: Chaetocin is a fungal metabolite that possesses a potent antiproliferative activity in solid tumors by inducing cell death. Although recent studies have extended the role of chaetocin in tumors, the underlying molecular mechanisms such as the downstream cascade that induces cell death has not clearly been elucidated. In this study, we show that chaetocin is able to induce both apoptosis and autophagy in several hepatoma cell lines including HepG2, Hep3B and Huh7 cell lines. Moreover, we found that the inhibition of caspase-3/7 activity by z-VAD-fmk treatment was able to block chaetocin-mediated cell death, whereas blocking autophagy by Bafilomycin A1 or the knockdown of autophagy protein 5 enhanced cell death mediated by chaetocin. These findings suggest that chaetocin has a potent anticancer effect against hepatoma. Inhibition of autophagy may potentiate anticancer effects of chaetocin thus providing evidence that combined treatment with chaetocin and autophagy inhibitors will be an effective strategy for treating cancer.

SUBMITTER: Jung HJ

PROVIDER: S-EPMC5399187 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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The anticancer effect of chaetocin is enhanced by inhibition of autophagy.

Jung H-J HJ Seo I I Casciello F F Jacquelin S S Lane S W SW Suh S-Il SI Suh M-H MH Lee J S JS Baek W-K WK

Cell death & disease 20160218

Chaetocin is a fungal metabolite that possesses a potent antiproliferative activity in solid tumors by inducing cell death. Although recent studies have extended the role of chaetocin in tumors, the underlying molecular mechanisms such as the downstream cascade that induces cell death has not clearly been elucidated. In this study, we show that chaetocin is able to induce both apoptosis and autophagy in several hepatoma cell lines including HepG2, Hep3B and Huh7 cell lines. Moreover, we found th ...[more]

PMID: 26890137

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Project description:In recent years, with the increasing understanding of the role of autophagy in tumorigenesis and development, a steady stream of studies have demonstrated that both excessive induction and inhibition of autophagy could effectively improve the therapeutic efficacy against tumors during cytotoxic or molecularly targeted drug therapy. Among them, autophagy inhibition mediated by nanomaterials has become an appealing notion in nanomedicine therapeutics, since it can be exploited as an effective adjuvant in chemotherapy or as a potential anti-tumor agent. Herein, we constructed a pH-sensitive nanoplatform loaded with epirubicin (EPI) (mPEG-b-P(DPA-b-DMAEMA)/EPI), enabling effective autophagy inhibition in the process of tumor-targeting therapy and further sensitized the tumors to EPI. It was found that polycationic nanomicelles (PEDD-Ms) displayed specific localization in lysosomes after entering tumor cells and caused the impairment of lysosomal degradation capacity through lysosomal alkalization in a dose-dependent manner. HepG2 cells treated with PEDD-Ms displayed a large-scale accumulation of autophagosomes and LC3 (an autophagosome marker protein), and the degradation of the autophagy substrate p62 was also blocked, which indicated that these functional nanomicelles could significantly inhibit autophagy. Meanwhile, the typical morphological characteristics of autophagosomes were directly visualized by TEM. In vivo results also showed that the tumor-targeted and autophagy inhibition-associated nanoplatform therapy could effectively improve the therapeutic efficiency of EPI, which may be partially attributed to the fact that autophagy inhibition could enhance the sensitivity of tumor cells to EPI. Overall, we revealed the effect of polycationic nanomicelles on autophagic processes in tumor cells and explored their possible molecular mechanism, also considering the synergistic outcome between autophagy mediated by nanomaterials and chemotherapeutic drugs to improve the therapeutic effect on tumors.

Dataset Information

The anticancer effect of chaetocin is enhanced by inhibition of autophagy.

Publications

The anticancer effect of chaetocin is enhanced by inhibition of autophagy.

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