Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl-2 through activation of autophagy in MCF-7 cells

Akkoç, Yunus; Berrak, Özge; Arısan, Elif Damla; Obakan, Pinar; Gürkan, Ajda Çoker; Palavan-Ünsal, Narçın

doi:10.1016/j.biopha.2015.02.029

Cited by 77 publications

(54 citation statements)

References 54 publications

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“…As mentioned above in the MTT assay, unnatural amino acid methyl esters that were derived from the gossypol Schiff bases 14−18 displayed potent efficacy in the inhibition of cell growth in the MCF-7 cell line, which expresses moderate levels of Bcl-2 and Mcl-1 (Table 2). 22,23 This observation correlated with the binding data of compounds 14−18 for Bcl-2, which indicated that Bcl-2 was the potential target of these compounds. .…”

supporting

confidence: 68%

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

Yue

et al. 2016

ACS Med. Chem. Lett.

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A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins. KEYWORDS: Gossypol Schiff bases, linear amino acid esters, antiapoptotic proteins N atural polyphenols have received considerable attention because of their biological activity. 1 Gossypol, a polyphenol that is isolated from cotton seeds, has long been investigated for antitumor activity in addition to the reported antiviral (such as anti-HIV 2 and anti-H 5 N 1 3 ), antifungal, 4 and antimalarial 5 activity as well as the inhibition of trypanosome T. brucei activity. 6 (−)-Gossypol is currently in Phase II clinical trials and displays single-agent antitumor activity in patients with advanced malignancies. 7 The removal or mask of aldehyde groups has been shown to significantly reduce the toxicity of gossypol in humans. 8 As such, a variety of gossypol derivatives has been developed, including gossypol lactones, 9 gossypol nitriles, 5 gossypolone, 10 modification of the main structure of naphthalene, 7,11 etc. Among these, gossypol Schiff bases displayed widespread biological activities. The purpose of the introduction of the imine through the aldehyde was to reduce the toxicity of gossypol without a loss in the activity since the hydroxyl group appears to be essential for the activity in many cases. 12 However, from known results, the reported activities of aldehyde derived compounds, including gossypol Schiff bases, decreased dramatically compared with gossypol itself in terms of antitumor activity ( Figure 1A). 12−15 The antitumor activities of gossypol Schiff bases were improved slightly only when the framework of gossypol was changed into gossypolone ( Figure 1B). 15 The effects of the introduced substituents of gossypol Schiff bases on the antitumor activity were still ambiguous. As a matter of fact, an investigation of the mechanism of the gossypol Schiff bases was not pursued in these previous studies. On the other hand, studies have shown that gossypol may inhibit tumor cells by interacting with Bcl-2 family proteins, which are the central regulators of apoptosis (programmed cell-death). 16 The modulation of the antiapoptotic Bcl-2 family (Bcl-2 and ...

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supporting

confidence: 68%

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

Yue

et al. 2016

ACS Med. Chem. Lett.

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“…Forced overexpression of BCL-2 also blocked curcumin-induced autophagy in human breast cancer MCF-7 cells, through its inhibitory interactions with BECN1, as described in [146]. Pre-treatment of cells with PI3K inhibitor LY294002 enhanced curcumin-induced autophagy via modulating of autophagosome formation in MCF-7 cells [146]. ATG7 silencing further increased apoptotic potential of curcumin in wild type and BCL-2+ MCF-7 cells, as indicated in [146].…”

Section: Anticancer Natural Compounds and Autophagymentioning

confidence: 93%

“…Moreover, curcumin treatment resulted in the mitochondrial fission in human hepatocellular carcinoma HepG2 cells, reduced mitochondrial membrane potential and activated the mitochondria-mediated autophagy [150]. Forced overexpression of BCL-2 also blocked curcumin-induced autophagy in human breast cancer MCF-7 cells, through its inhibitory interactions with BECN1, as described in [146]. Pre-treatment of cells with PI3K inhibitor LY294002 enhanced curcumin-induced autophagy via modulating of autophagosome formation in MCF-7 cells [146].…”

Section: Anticancer Natural Compounds and Autophagymentioning

confidence: 99%

Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells

Guamán-Ortiz

Orellana²,

Ratovitski³

2017

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Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.

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“…First, it remains controversial whether such inducible autophagy serves as a pro-survival or pro-death mechanism. It has been reported that autophagy inhibition enhances Curcumin-caused cell death, indicting the pro-survival function of autophagy [18, 19]. In contrast, Curcumin has been shown to induce autopahgic cell death [20].…”

Section: Introductionmentioning

confidence: 99%

Curcumin targets the TFEB-lysosome pathway for induction of autophagy

Wang

et al. 2016

Oncotarget

113

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Curcumin is a hydrophobic polyphenol derived from the herb Curcumalonga and its wide spectrum of pharmacological activities has been widely studied. It has been reported that Curcumin can induce autophagy through inhibition of the Akt-mTOR pathway. However, the effect of Curcumin on lysosome remains largely elusive. In this study, we first found that Curcumin treatment enhances autophagic flux in both human colon cancer HCT116 cells and mouse embryonic fibroblasts (MEFs). Moreover, Curcumin treatment promotes lysosomal function, evidenced by the increased lysosomal acidification and enzyme activity. Second, Curcumin is capable of suppressing the mammalian target of rapamycin (mTOR). Interestingly, Curcumin fails to inhibit mTOR and to activate lysosomal function in Tsc2−/−MEFs with constitutive activation of mTOR, indicating that Curcumin-mediated lysosomal activation is achieved via suppression of mTOR. Third, Curcumin treatment activates transcription factor EB (TFEB), a key nuclear transcription factor in control of autophagy and lysosome biogenesis and function, based on the following observations: (i) Curcumin directly binds to TFEB, (ii) Curcumin promotes TFEB nuclear translocation; and (iii) Curcumin increases transcriptional activity of TFEB. Finally, inhibition of autophagy and lysosome leads to more cell death in Curcumin-treated HCT116 cells, suggesting that autophagy and lysosomal activation serves as a cell survival mechanism to protect against Curcumin-mediated cell death. Taken together, data from our study provide a novel insight into the regulatory mechanisms of Curcumin on autophagy and lysosome, which may facilitate the development of Curcumin as a potential cancer therapeutic agent.

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Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl-2 through activation of autophagy in MCF-7 cells

Cited by 77 publications

References 54 publications

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells

Curcumin targets the TFEB-lysosome pathway for induction of autophagy

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