Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells

Timme, Cindy R.; Gruidl, Mike; Yeatman, Timothy J.

doi:10.1007/s10495-013-0883-x

Cited by 30 publications

(24 citation statements)

References 42 publications

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“…It is well known Notch pathway interacts with many different signaling cascades to regulate critical cellular processes (26). In different cancers, the inhibition of Notch-1 has been reported to induce G2/M cell cycle arrest (33), upregulate apoptosis via anti- BCL-XL,BCL-2 (34, 35), and impair phosphorylation of MEK (36) and AKT (37). Our results reflect that GSI treatment of prostate cancer involves many of these activities and thus suggest that the anti-tumor effects of Notch inhibition in prostate cancer involves multiple mechanisms that culminate in an overall inhibition of tumor growth through both inhibition of proliferation and induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer

Cui

Dai

Keller

et al. 2015

Clinical Cancer Research

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Purpose To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a γ-secretase inhibitor (GSI), PF-03084014. Experimental Design The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and -resistant CRPC cell lines in vitro and in murine models. Both soft tissue and bone sites were evaluated in vivo. Impacts on cell proliferation, apoptosis, cancer stem cells and angiogenesis were evaluated. Results The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and -resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014-induced inhibition of Notch pathway signaling; decreased survival signals (Cyclin E; MEK-ERK, PI3K-AKT, EGFR and NF-κB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved-caspase 3); reduction of microvessel density; reduced epithelial mesenchymal transition; and reduction of cancer stem-like cells in the tumor. Conclusion These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC.

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Section: Discussionmentioning

confidence: 99%

Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer

Cui

Dai

Keller

et al. 2015

Clinical Cancer Research

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“…Caspase-cascade is controlled by some molecules and is crucial in cell apoptosis. The ratio of Bax/Bcl-2 usually determined the cell apoptosis (Timme et al, 2013;Yang et al, 2013) and activated caspase-cascade or not. In our present study, mIDH1 and wIDH1 over expression didn't cause apoptosis changes under routine condition.…”

Section: Discussionmentioning

confidence: 99%

IDH1 Overexpression Induced Chemotherapy Resistance and IDH1 Mutation Enhanced Chemotherapy Sensitivity in Glioma Cells in Vitro and in Vivo

Wang¹,

Dong²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Isocitrate dehydrogenase (IDH) is of great importance in cell metabolism and energy conversion. IDH mutation in glioma cells is reported to be associated with an increased overall survival. However, effects biological behavior of therapy of gliomas are unclear. Here, we investigated the influence of wild-type and mutated IDH genes on glioma cell biological behavior and response to chemotherapy. Relevant mechanisms were further explored. We designed our study on the background of the IDHR132H mutation. Stable cell lines were constructed by transfection. The CCK-8 method was used to assess cell proliferation, flow cytometry for the cell cycle and cell apoptosis, and the transwell method for cell invasion. Nude mouse models were employed to determine tumorigenesis and sensitivity to chemotherapy. Western blotting was used to detect relevant protein expression levels. We found that overexpression of wild IDH1 gene did not cause changes in the cell cycle, apoptosis and invasion ability. However, it resulted in chemotherapy resistance to a high dose of temozolomide (TMZ) in vivo and in vitro. The IDH1 mutation caused cell cycle arrest in G1 stage and a reduction of proliferation and invasion ability, while raising sensitivity to chemotherapy. This may provide an explanation for the better prognosis of IDH1 mutated glioma patients and the relative worse prognosis of their wild-type IDH1 counterparts. We also expect IDH1 mutations may be optimized as new targets to improve the prognosis of glioma patients.

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“…Shi et al (34) reported that oxaliplatininduced colorectal cancer cell apoptosis was enhanced by apoptosis stimulated protein of p53-2 (ASPP2) via inhibition of autophagy. Timme et al (35) showed that increased protein levels of Mcl-1 and/or Bcl-xL as well as reduction in Bax and Bak activation attenuated oxaliplatin-induced apoptosis in human colon cancer cells. Shan et al (36) indicated that downregulation of RIP1 promoted oxaliplatin-induced apoptosis in tongue squamous cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Gefitinib enhances oxaliplatin-induced apoptosis mediated by Src and PKC-modulated gap junction function

Dong

et al. 2016

Oncology Reports

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Chemotherapeutic drug-induced apoptosis is enhanced by gap junction intercellular communication (GJIC) in a variety of tumor cells. Oxaliplatin and gefitinib are the most widely used chemotherapeutic drugs. However, the synergistic influence remains unknown in testicular cancer chemotherapy. The aim of the present study was to investigate the apoptosis induced by oxaliplatin combined with gefitinib and the potential mechanisms in I-10 testicular cancer cells. The results showed that gefitinib significantly enhanced oxaliplatin-induced apoptosis. Furthermore, the ratio of Bcl-2/Bax and the cleavage of caspase-3 and -9 were increased by gefitinib during oxaliplatin-induced apoptosis. The oxaliplatin-induced apoptosis was enhanced through the upregulation of gap junction (GJ) channels composed of connexin 43 (Cx43) by gefitinib. The mechanism of GJIC enhancement involved the suppression by gefitinib of the expression levels of Src and PKC, which phosphorylate Cx43 and reduce GJIC. PP2 (Src inhibitor) and GF109203X (PKC inhibitor) also enhanced GJIC function. Our findings demonstrated that gefitinib enhanced oxaliplatin-induced apoptosis in I-10 cells and gefitinib upregulated the GJIC by inhibiting Src and PKC-modulated Cx43 phosphorylation.

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Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells

Cited by 30 publications

References 42 publications

Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer

Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer

IDH1 Overexpression Induced Chemotherapy Resistance and IDH1 Mutation Enhanced Chemotherapy Sensitivity in Glioma Cells in Vitro and in Vivo

Gefitinib enhances oxaliplatin-induced apoptosis mediated by Src and PKC-modulated gap junction function

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