(±)-Gossypol induces apoptosis and autophagy in head and neck carcinoma cell lines and inhibits the growth of transplanted salivary gland cancer cells in BALB/<i>c</i> mice

Benvenuto, Monica; Mattera, Rosanna; Masuelli, Laura; Taffera, Gloria; Andracchio, Orlando; Tresoldi, Ilaria; Lido, Paolo; Giganti, Maria Gabriella; Godos, Justyna; Modesti, Andrea; Bei, Roberto

doi:10.1080/09637486.2016.1236077

Cited by 24 publications

(27 citation statements)

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“…AT-101 is a BH3 mimetic compound ( Opydo-Chanek et al, 2017 ). The Bcl-2 family proteins (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1/BFL-1) interact with BH3 proteins, such as Bax or Beclin-1, and regulate various intracellular pathways, including apoptosis and autophagy ( Maiuri et al, 2007 ; Sinha and Levine, 2008 ; Vela et al, 2013 ; Benvenuto et al, 2017 ). It has been demonstrated that gossypol binds to the BH3 binding groove of anti-apoptotic Bcl-2 proteins, thus inhibiting the anti-apoptotic function of Bcl-2, Bcl-xl, and Mcl-1, and inducing apoptosis of cancer cells ( Kang and Reynolds, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we demonstrated that AT-101 was also able to activate Beclin-1-dependent autophagy. Previous studies reported the in vitro induction of autophagy following gossypol treatment in breast cancer ( Gao et al, 2010 ), malignant glioma ( Voss et al, 2010 ), melanoma ( Jang and Lee, 2014 ), gastric cancer ( Wei et al, 2016 ), head and neck cancer ( Benvenuto et al, 2017 ), colon cancer ( Lu et al, 2017 ). In our study, AT-101 stimulated autophagy, but the process was then blocked, as indicated by the increase of the levels of p62/SQSMT1 and was coincident with the activation of apoptosis in MM-B1, H-Meso-1 and #40a cells.…”

Section: Discussionmentioning

confidence: 99%

“…A study reported that activation of the JNK pathway by gossypol was required for the induction of apoptosis in head and neck squamous cell carcinoma and in human leukemic cells ( Zerp et al, 2009 ). In addition, we previously demonstrated that gossypol-induced apoptosis was mediated by the activation of JNK and p38 in head and neck cancer cells ( Benvenuto et al, 2017 ). Here we showed an increased expression of p54 and p46 JNK phosphorylation in all AT-101-treated cells.…”

Section: Discussionmentioning

confidence: 99%

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Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma

et al. 2018

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Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the in vivo anti-tumor activities of AT-101 in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space. AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of AT-101 in inducing the apoptosis of MM cells, MM cells were simultaneously treated with AT-101 and with the caspase inhibitor, Z-VAD-FMK. Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone. This result corroborates the induction of cell death by apoptosis following treatment with AT-101. Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with AT-101 was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our in vivo results showed that the intraperitoneal administration of AT-101 increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing AT-101 as an anticancer agent in combination with standard therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma

et al. 2018

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“…Once activated, p38 MAPKs phosphorylate the serine/threonine residues of their substrates, which include several transcription factors as well as protein kinases (38). It has been reported that the activation and phosphorylation of p38 MAPK mediates the anticancer activity in numerous malignant cancers such as pancreatic (39) and gastric cancer (40), and head and neck carcinoma (41).…”

Section: Discussionmentioning

confidence: 99%

Tetrandrine inhibits the proliferation of human osteosarcoma cells by upregulating the PTEN pathway

Tian

Zhang

et al. 2017

Oncology Reports

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Tetrandrine (TET) is a natural product isolated from the Chinese herb Stephania tetrandra S. Moore and has been reported to have antiproliferation and apoptosis-inducing activity in various malignant tumor cells. However, the exact molecular mechanisms underlying these effects remain unclear. In the present study, we tested the antiproliferation effect of TET on osteosarcoma (OS) 143B cells and explored the possible potential molecular mechanism in this process. Using CCK-8 assay and flow cytometry, we found that TET inhibited proliferation, induced apoptosis and arrested the cell cycle of the 143B cells. Using a xenograft tumor model of human OS, tetrandrine was found to inhibit tumor growth in vivo. TET increased the protein level of phosphatase and tensin homolog (PTEN) and decreased its phosphorylation as detected by western blot analysis and immunohistochemistry.Overexpression of PTEN strengthened the anticancer effect of TET, while knockdown of PTEN attenuated it. Meanwhile, TET activated p38 MAPK and increased its phosphorylation. Our findings suggest that TET may be a potential anticancer drug for OS. In addition, its effects may be mediated by the upregulation of PTEN. Moreover the expression alteration of PTEN and p-PTEN was mediated by the TET-induced activation of p38 MAPK in a direct or indirect manner.

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“…The percentage survival of the cultures treated with API was calculated by normalizing their O.D. values to those of control cultures treated with DMSO (Benvenuto et al, 2016b; Masuelli et al, 2017). The experiments were performed in triplicate and repeated three times.…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma

et al. 2017

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Malignant mesothelioma (MM) is a tumor arising from mesothelium. MM patients’ survival is poor. The polyphenol 4′,5,7,-trihydroxyflavone Apigenin (API) is a “multifunctional drug”. Several studies have demonstrated API anti-tumoral effects. However, little is known on the in vitro and in vivo anti-tumoral effects of API in MM. Thus, we analyzed the in vitro effects of API on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, and autophagy of human and mouse MM cells. We evaluated the in vivo anti-tumor activities of API in mice transplanted with MM #40a cells forming ascites. API inhibited in vitro MM cells survival, increased reactive oxygen species intracellular production and induced DNA damage. API activated apoptosis but not autophagy. API-induced apoptosis was sustained by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of both caspase 9 and caspase 8, cleavage of PARP-1, and increase of the percentage of cells in subG1 phase. API treatment affected the phosphorylation of ERK1/2, JNK and p38 MAPKs in a cell-type specific manner, inhibited AKT phosphorylation, decreased c-Jun expression and phosphorylation, and inhibited NF-κB nuclear translocation. Intraperitoneal administration of API increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of tumor growth. Our findings may have important implications for the design of MM treatment using API.

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(±)-Gossypol induces apoptosis and autophagy in head and neck carcinoma cell lines and inhibits the growth of transplanted salivary gland cancer cells in BALB/c mice

Cited by 24 publications

References 71 publications

Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma

Effect of the BH3 Mimetic Polyphenol (–)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma

Tetrandrine inhibits the proliferation of human osteosarcoma cells by upregulating the PTEN pathway

In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma

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