Sorafenib induces apoptotic cell death in human non-small cell lung cancer cells by down-regulating mammalian target of rapamycin (mTOR)-dependent survivin expression

Kim, Young-Sun; Jin, Hyeon‐Ok; Seo, Sung‐Keum; Woo, Seung Kyoon; Choe, Taeboo; An, Sungkwan; Hong, Seok‐Il; Lee, Su‐Jae; Lee, Kee-Ho; Park, In-Chul

doi:10.1016/j.bcp.2011.04.011

Cited by 44 publications

(39 citation statements)

References 24 publications

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“…Inhibitors targeting this pathway may reduce cellular antiapoptotic activity by downregulating survivin expression, thereby increasing the efficacy of cotherapies. Recent studies showed that upregulation of survivin by gene transfer enhanced resistance to TRAILinduced apoptosis (Kim et al, 2011;Raviv et al, 2011), whereas transfection with survivin antisense rendered resistant cells susceptible to TRAIL-induced apoptosis (Li et al, 2005;Azuhata et al, 2006). In addition, because it was shown that Mcl-1 downregulation could cooperate with TRAIL (Meng et al, 2007;Kim et al, 2008) and that its inhibition could be required for apoptosis induction and promoted by YM-155 treatment , we hypothesized that Bak immunoprecipitates using monoclonal anti-Bak (Ab-1; Calbiochem) were subjected to Western blot (WB) analysis using polyclonal anti-Bak antibody (Cell Signaling Technology).…”

Section: Discussionmentioning

confidence: 99%

“…We recently showed that YM-155 suppressed survivin expression, with little effect on the expression levels of other IAP family members and inhibited growth and viability of certain glioma cell lines, in addition to downregulating myeloid cell leukemia sequence 1 (Mcl-1) levels . Recent studies showed that upregulation of survivin by gene transfer enhanced resistance to TRAIL-induced apoptosis (Kim et al, 2011;Raviv et al, 2011), whereas transfection with survivin antisense enhanced sensitivity to TRAIL-induced apoptosis (Li et al, 2005;Azuhata et al, 2006). Because Mcl-1 is also a critical mediator of cellular resistance to various anticancer therapies, including suppression of TRAILinduced cell death (Kobayashi et al, 2005;Ricci et al, 2007;Kim et al, 2008;Oh et al, 2012), we questioned whether YM-155 could sensitize resistant glioma cells to TRAIL, either by inhibition of survivin or Mcl-1 or both.…”

Section: Introductionmentioning

confidence: 99%

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Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway

Premkumar

Jane

Foster

et al. 2013

J Pharmacol Exp Ther

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Induction of apoptosis by the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor therapy. However, not all tumor cells are sensitive to TRAIL, highlighting the need for strategies to overcome TRAIL resistance. Inhibitor of apoptosis family member survivin is constitutively activated in various cancers and blocks apoptotic signaling. Recently, we demonstrated that YM-155, a small molecule inhibitor, downregulates not only survivin in gliomas but also myeloid cell leukemia sequence 1 (Mcl-1), and it upregulates proapoptotic Noxa levels. Because Mcl-1 and survivin are critical mediators of resistance to various anticancer therapies, we questioned whether YM-155 could sensitize resistant glioma cells to TRAIL. To address this hypothesis, we combined YM-155 with TRAIL and examined the effects on cell survival and apoptotic signaling. TRAIL or YM-155 individually induced minimal killing in highly resistant U373 and LNZ308 cell lines, but combining TRAIL with YM-155 triggered a synergistic proapoptotic response, mediated through mitochondrial dysfunction via activation of caspases-8, -9, -7, -3, poly-ADPribose polymerase, and Bid. Apoptosis induced by combination treatments was blocked by caspase-8 and pan-caspase inhibitors. In addition, knockdown of Mcl-1 by RNA interference overcame apoptotic resistance to TRAIL. Conversely, silencing Noxa by RNA interference reduced the combined effects of YM-155 and TRAIL on apoptosis. Mechanistically, these findings indicate that YM-155 plays a role in counteracting glioma cell resistance to TRAIL-induced apoptosis by downregulating Mcl-1 and survivin and amplifying mitochondrial signaling through intrinsic and extrinsic apoptotic pathways. The significantly enhanced antitumor activity of the combination of YM-155 and TRAIL may have applications for therapy of malignant glioma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway

Premkumar

Jane

Foster

et al. 2013

J Pharmacol Exp Ther

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“…Furthermore, high levels of mTOR and its transducer p70S6K have been consistently correlated with a poorer osteosarcoma prognosis (17). In light of the involvement of mTOR in osteosarcoma progression and metastatization, we investigated whether or not sorafenib treatment might affect the mTOR pathway, and if the specific inhibition of mTOR might raise the potential of sorafenib activity (18,19).…”

Section: Introductionmentioning

confidence: 99%

“…We asked whether sorafenib treatment might affect the mTOR pathway, and if the specific inhibition of mTOR might raise the potential of sorafenib activity (18,19). At least 2 mTOR inhibitors, namely, the analogs of rapamycin ridaforolimus and everolimus, have shown minimal activity in clinical and preclinical osteosarcoma therapy, respectively (20,21).…”

Section: Introductionmentioning

confidence: 99%

The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

Pignochino

Dell'Aglio²,

Basiricò³

et al. 2013

Clinical Cancer Research

107

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“…3F), which would inhibit mTOR signaling. Recent studies show that survivin is regulated by PI3K/Akt/p70s6K1 pathway (20), and some Raf kinase inhibitors could induce mTOR-dependent survivin downregulation (21). Therefore, we went further to investigate the effects of ch282-5 on mTOR, Akt, and p70s6k pathway.…”

Section: Ch282-5 Regulates Bcl-2 and Iap Family Proteins And Inducesmentioning

confidence: 99%

A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria

Wang

Zhang

Yan

et al. 2016

Clinical Cancer Research

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Purpose: Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing antiapoptotic proteins, have been shown to inhibit the growth of various human cancer cells in culture and xenograft models. Here, we evaluated the antitumor efficacy of a novel gossypol derivative and BH3 mimetic ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone) in colon cancer models. Several innovative combination strategies were also explored and elaborated.Experimental Design: Ch282-5 was synthesized by modifying the active aldehyde groups and R groups of gossypol according to a computer-aided drug design program. The stability of ch282-5 was examined by high-performance liquid chromatography, and cytotoxic effects of ch282-5 on colon cancer cells were assessed by MTS assay. Activation of mitochondrial apoptotic pathway by ch282-5 was evidenced with a series of molecular biology techniques. In vivo antitumor activity of ch282-5 and its combination with chloroquine, rapamycin, oxaliplatin, and ABT-263 was also evaluated in colon cancer xenograft models and experimental liver metastasis models.Results: Ch282-5 showed antiproliferative and pro-cell death activity against colon cancer cells both in vitro and in vivo, and the response to the drug correlated with inhibition of antiapoptotic Bcl-2 proteins, induction of mitochondria-dependent apoptotic pathway, and disruption of mitophagy and mTOR pathway. Ch282-5 also suppressed liver metastasis produced by intrasplenic injection of colon cancer cells. Furthermore, ch282-5 could potentiate the effectiveness of oxaliplatin and rescue ABT-263 efficacy by downregulation of Mcl-1 and elevation of platelet number.Conclusions: These findings provide a rational basis for clinical investigation of this highly promising BH3 mimetic in colon cancer.

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Sorafenib induces apoptotic cell death in human non-small cell lung cancer cells by down-regulating mammalian target of rapamycin (mTOR)-dependent survivin expression

Cited by 44 publications

References 24 publications

Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway

Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway

The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria

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