The Experts below are selected from a list of 4530 Experts worldwide ranked by ideXlab platform
Akinori Sato - One of the best experts on this subject based on the ideXlab platform.
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Metformin Augments Panobinostat's Anti-Bladder Cancer Activity by Activating AMP-Activated Protein Kinase.
Translational oncology, 2019Co-Authors: Kazuki Okubo, Makoto Isono, Takako Asano, Akinori SatoAbstract:Abstract Panobinostat, a histone deacetylase inhibitor, induces histone acetylation and acts against cancer but attenuates its anticancer activity by activating the mammalian target of rapamycin (mTOR) pathway. AMP-activated protein kinase (AMPK) is a cellular energy sensor that reportedly inhibits the mTOR pathway. The antidiabetic drug metformin is also a potent AMPK activator and we investigated whether it augmented Panobinostat's antineoplastic activity in bladder cancer cells (UMUC3, J82, T24 and MBT-2). Metformin enhanced Panobinostat-induced apoptosis and the combination inhibited the growth of bladder cancer cells cooperatively in vitro and in vivo. As expected, metformin increased the phosphorylation of AMPK and decreased the Panobinostat-caused phosphorylation of S6 ribosomal protein, thus inhibiting the Panobinostat-activated mTOR pathway. The AMPK activation was shown to play a pivotal role in the combination's action because the AMPK inhibitor compound C attenuated the combination's anticancer activity. Furthermore, the AMPK activation by metformin enhanced Panobinostat-induced histone and non-histone acetylation. This acetylation was especially remarkable in the proteins in the detergent-insoluble fraction, which would be expected if the combination also induced endoplasmic reticulum stress.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells
BMC Urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor Panobinostat hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90. We investigated whether combining Panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with Panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protein accumulation were assessed. The combination of Panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). It also suppressed colony formation significantly (p <0.05). In a murine subcutaneous tumor model, a 10-day treatment was well tolerated and inhibited tumor growth significantly (p <0.05). Enhanced acetylation of the HDAC6 substrate alpha-tubulin was consistent with the suppression of HDAC6 activity by Panobinostat, and the combination was shown to induce ER stress and ubiquitinated protein accumulation synergistically. Panobinostat inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and ubiquitinated protein accumulation. The current study provides a basis for testing the combination in patients with advanced renal cancer.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells.
BMC urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor Panobinostat hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90. We investigated whether combining Panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with Panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protein accumulation were assessed. The combination of Panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes
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Ritonavir acts synergistically with Panobinostat to enhance histone acetylation and inhibit renal cancer growth
Molecular and clinical oncology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:There is currently no curative treatment for advanced renal cancer. Enhancing histone acetylation is a promising epigenetic-based therapy for cancer; however, in solid tumors, the efficacy of histone deacetylase (HDAC) inhibitors alone is limited. The human immunodeficiency virus protease inhibitor ritonavir is also a CYP3A4 inhibitor and we hypothesized that combining ritonavir with the HDAC inhibitor Panobinostat, one of the substrates of CYP3A4, may effectively eliminate renal cancer cells by enhancing the activity of Panobinostat. The combination of ritonavir and Panobinostat synergistically inhibited cancer cell growth and cancer cell colony formation, while only slightly inhibiting the growth of renal proximal tubule epithelial cells. This combination significantly induced apoptosis in cancer cells and this apoptosis was considered to be caspase-dependent, since the pan-caspase inhibitor Z-VAD-FMK reduced the number of Annexin V-positive cells. In murine subcutaneous xenograft models using Caki-1 cells, a 10-day treatment with the combination of ritonavir and Panobinostat significantly inhibited tumor growth. Panobinostat alone increased histone acetylation in a dose-dependent manner and the co-administration of ritonavir synergistically enhanced this acetylation. Furthermore, this combination inhibited the expression of HDACs, which may also play a role in the enhancement of histone acetylation. Thus, the present study may provide a basis for testing the combination of ritonavir and Panobinostat for patients with advanced renal cancer.
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167 RITONAVIR INTERACTS WITH Panobinostat TO ENHANCE HISTONE ACETYLATION AND INHIBIT RENAL CANCER GROWTH SYNERGISTICALLY
The Journal of Urology, 2013Co-Authors: Akinori Sato, Takako Asano, Keiichi Ito, Tomohiko AsanoAbstract:INTRODUCTION AND OBJECTIVES: Histone acetylation is an attractive epigenetic approach to cancer treatment, but the efficacy of histone deacetylase (HDAC) inhibitors as anticancer agents is limited, especially in solid tumors. The HDAC inhibitor Panobinostat is partly metabolized by CYP3A4, and the HIV protease inhibitor ritonavir also inhibits CYP3A4. We therefore thought that combining ritonavir with Panobinostat would kill cancer cells effectively by enhancing Panobinostat activity. METHODS: Renal cancer cells (Caki-1, ACHN, 769-P, 786-O) and renal proximal tubule epithelial cells (RPTEC) were treated with clinically feasible concentrations of ritonavir (25-50 M) and Panobinostat (10-50 nM). Cell viability and clonogenicity were assessed by MTS assay and colony formation assay. A murine subcutaneous tumor model was used to evaluate in vivo efficacy, flow cytometry was used to detect apoptosis, and western blot analysis was used to assess the expression of HDACs and acetylated histone. Combination indexes (CI) were calculated by the Chou-Talalay method. RESULTS: The combination of ritonavir and Panobinostat induced apoptosis and inhibited cancer cell growth synergistically (CI 1). It also inhibited colony formation significantly (P 0.05). On the other hand, induction of apoptosis and cell growth inhibition were minimal in RPTEC. The combination-induced apoptosis was thought to be caspase-dependent because the pancaspase inhibitor Z-VAD-FMK reduced the number of the annexin-V positive cells produced by the combination. In murine subcutaneous tumor models using Caki-1 cells, a 10-day treatment with a combination of Panobinostat (2 mg/kg) and ritonavir (50 mg/kg) inhibited tumor growth significantly (P 0.05). Panobinostat induced histone acetylation in a dose-dependent fashion, and ritonavir enhanced this acetylation synergistically. The combination also inhibited the expression of HDACs, and this might further enhance histone acetylation. Interestingly, the combination-induced histone acetylation and apoptosis were also seen in in-vivo tumor specimens. CONCLUSIONS: Ritonavir and Panobinostat inhibited renal cancer growth synergistically by enhancing histone acetylation. The present study provides a basis for testing the combination in clinical settings.
Tomohiko Asano - One of the best experts on this subject based on the ideXlab platform.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells
BMC Urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor Panobinostat hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90. We investigated whether combining Panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with Panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protein accumulation were assessed. The combination of Panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). It also suppressed colony formation significantly (p <0.05). In a murine subcutaneous tumor model, a 10-day treatment was well tolerated and inhibited tumor growth significantly (p <0.05). Enhanced acetylation of the HDAC6 substrate alpha-tubulin was consistent with the suppression of HDAC6 activity by Panobinostat, and the combination was shown to induce ER stress and ubiquitinated protein accumulation synergistically. Panobinostat inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and ubiquitinated protein accumulation. The current study provides a basis for testing the combination in patients with advanced renal cancer.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells.
BMC urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor Panobinostat hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90. We investigated whether combining Panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with Panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protein accumulation were assessed. The combination of Panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes
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Ritonavir acts synergistically with Panobinostat to enhance histone acetylation and inhibit renal cancer growth
Molecular and clinical oncology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:There is currently no curative treatment for advanced renal cancer. Enhancing histone acetylation is a promising epigenetic-based therapy for cancer; however, in solid tumors, the efficacy of histone deacetylase (HDAC) inhibitors alone is limited. The human immunodeficiency virus protease inhibitor ritonavir is also a CYP3A4 inhibitor and we hypothesized that combining ritonavir with the HDAC inhibitor Panobinostat, one of the substrates of CYP3A4, may effectively eliminate renal cancer cells by enhancing the activity of Panobinostat. The combination of ritonavir and Panobinostat synergistically inhibited cancer cell growth and cancer cell colony formation, while only slightly inhibiting the growth of renal proximal tubule epithelial cells. This combination significantly induced apoptosis in cancer cells and this apoptosis was considered to be caspase-dependent, since the pan-caspase inhibitor Z-VAD-FMK reduced the number of Annexin V-positive cells. In murine subcutaneous xenograft models using Caki-1 cells, a 10-day treatment with the combination of ritonavir and Panobinostat significantly inhibited tumor growth. Panobinostat alone increased histone acetylation in a dose-dependent manner and the co-administration of ritonavir synergistically enhanced this acetylation. Furthermore, this combination inhibited the expression of HDACs, which may also play a role in the enhancement of histone acetylation. Thus, the present study may provide a basis for testing the combination of ritonavir and Panobinostat for patients with advanced renal cancer.
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167 RITONAVIR INTERACTS WITH Panobinostat TO ENHANCE HISTONE ACETYLATION AND INHIBIT RENAL CANCER GROWTH SYNERGISTICALLY
The Journal of Urology, 2013Co-Authors: Akinori Sato, Takako Asano, Keiichi Ito, Tomohiko AsanoAbstract:INTRODUCTION AND OBJECTIVES: Histone acetylation is an attractive epigenetic approach to cancer treatment, but the efficacy of histone deacetylase (HDAC) inhibitors as anticancer agents is limited, especially in solid tumors. The HDAC inhibitor Panobinostat is partly metabolized by CYP3A4, and the HIV protease inhibitor ritonavir also inhibits CYP3A4. We therefore thought that combining ritonavir with Panobinostat would kill cancer cells effectively by enhancing Panobinostat activity. METHODS: Renal cancer cells (Caki-1, ACHN, 769-P, 786-O) and renal proximal tubule epithelial cells (RPTEC) were treated with clinically feasible concentrations of ritonavir (25-50 M) and Panobinostat (10-50 nM). Cell viability and clonogenicity were assessed by MTS assay and colony formation assay. A murine subcutaneous tumor model was used to evaluate in vivo efficacy, flow cytometry was used to detect apoptosis, and western blot analysis was used to assess the expression of HDACs and acetylated histone. Combination indexes (CI) were calculated by the Chou-Talalay method. RESULTS: The combination of ritonavir and Panobinostat induced apoptosis and inhibited cancer cell growth synergistically (CI 1). It also inhibited colony formation significantly (P 0.05). On the other hand, induction of apoptosis and cell growth inhibition were minimal in RPTEC. The combination-induced apoptosis was thought to be caspase-dependent because the pancaspase inhibitor Z-VAD-FMK reduced the number of the annexin-V positive cells produced by the combination. In murine subcutaneous tumor models using Caki-1 cells, a 10-day treatment with a combination of Panobinostat (2 mg/kg) and ritonavir (50 mg/kg) inhibited tumor growth significantly (P 0.05). Panobinostat induced histone acetylation in a dose-dependent fashion, and ritonavir enhanced this acetylation synergistically. The combination also inhibited the expression of HDACs, and this might further enhance histone acetylation. Interestingly, the combination-induced histone acetylation and apoptosis were also seen in in-vivo tumor specimens. CONCLUSIONS: Ritonavir and Panobinostat inhibited renal cancer growth synergistically by enhancing histone acetylation. The present study provides a basis for testing the combination in clinical settings.
Takako Asano - One of the best experts on this subject based on the ideXlab platform.
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Metformin Augments Panobinostat's Anti-Bladder Cancer Activity by Activating AMP-Activated Protein Kinase.
Translational oncology, 2019Co-Authors: Kazuki Okubo, Makoto Isono, Takako Asano, Akinori SatoAbstract:Abstract Panobinostat, a histone deacetylase inhibitor, induces histone acetylation and acts against cancer but attenuates its anticancer activity by activating the mammalian target of rapamycin (mTOR) pathway. AMP-activated protein kinase (AMPK) is a cellular energy sensor that reportedly inhibits the mTOR pathway. The antidiabetic drug metformin is also a potent AMPK activator and we investigated whether it augmented Panobinostat's antineoplastic activity in bladder cancer cells (UMUC3, J82, T24 and MBT-2). Metformin enhanced Panobinostat-induced apoptosis and the combination inhibited the growth of bladder cancer cells cooperatively in vitro and in vivo. As expected, metformin increased the phosphorylation of AMPK and decreased the Panobinostat-caused phosphorylation of S6 ribosomal protein, thus inhibiting the Panobinostat-activated mTOR pathway. The AMPK activation was shown to play a pivotal role in the combination's action because the AMPK inhibitor compound C attenuated the combination's anticancer activity. Furthermore, the AMPK activation by metformin enhanced Panobinostat-induced histone and non-histone acetylation. This acetylation was especially remarkable in the proteins in the detergent-insoluble fraction, which would be expected if the combination also induced endoplasmic reticulum stress.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells
BMC Urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor Panobinostat hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90. We investigated whether combining Panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with Panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protein accumulation were assessed. The combination of Panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). It also suppressed colony formation significantly (p <0.05). In a murine subcutaneous tumor model, a 10-day treatment was well tolerated and inhibited tumor growth significantly (p <0.05). Enhanced acetylation of the HDAC6 substrate alpha-tubulin was consistent with the suppression of HDAC6 activity by Panobinostat, and the combination was shown to induce ER stress and ubiquitinated protein accumulation synergistically. Panobinostat inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and ubiquitinated protein accumulation. The current study provides a basis for testing the combination in patients with advanced renal cancer.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells.
BMC urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor Panobinostat hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90. We investigated whether combining Panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with Panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protein accumulation were assessed. The combination of Panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes
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Ritonavir acts synergistically with Panobinostat to enhance histone acetylation and inhibit renal cancer growth
Molecular and clinical oncology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:There is currently no curative treatment for advanced renal cancer. Enhancing histone acetylation is a promising epigenetic-based therapy for cancer; however, in solid tumors, the efficacy of histone deacetylase (HDAC) inhibitors alone is limited. The human immunodeficiency virus protease inhibitor ritonavir is also a CYP3A4 inhibitor and we hypothesized that combining ritonavir with the HDAC inhibitor Panobinostat, one of the substrates of CYP3A4, may effectively eliminate renal cancer cells by enhancing the activity of Panobinostat. The combination of ritonavir and Panobinostat synergistically inhibited cancer cell growth and cancer cell colony formation, while only slightly inhibiting the growth of renal proximal tubule epithelial cells. This combination significantly induced apoptosis in cancer cells and this apoptosis was considered to be caspase-dependent, since the pan-caspase inhibitor Z-VAD-FMK reduced the number of Annexin V-positive cells. In murine subcutaneous xenograft models using Caki-1 cells, a 10-day treatment with the combination of ritonavir and Panobinostat significantly inhibited tumor growth. Panobinostat alone increased histone acetylation in a dose-dependent manner and the co-administration of ritonavir synergistically enhanced this acetylation. Furthermore, this combination inhibited the expression of HDACs, which may also play a role in the enhancement of histone acetylation. Thus, the present study may provide a basis for testing the combination of ritonavir and Panobinostat for patients with advanced renal cancer.
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167 RITONAVIR INTERACTS WITH Panobinostat TO ENHANCE HISTONE ACETYLATION AND INHIBIT RENAL CANCER GROWTH SYNERGISTICALLY
The Journal of Urology, 2013Co-Authors: Akinori Sato, Takako Asano, Keiichi Ito, Tomohiko AsanoAbstract:INTRODUCTION AND OBJECTIVES: Histone acetylation is an attractive epigenetic approach to cancer treatment, but the efficacy of histone deacetylase (HDAC) inhibitors as anticancer agents is limited, especially in solid tumors. The HDAC inhibitor Panobinostat is partly metabolized by CYP3A4, and the HIV protease inhibitor ritonavir also inhibits CYP3A4. We therefore thought that combining ritonavir with Panobinostat would kill cancer cells effectively by enhancing Panobinostat activity. METHODS: Renal cancer cells (Caki-1, ACHN, 769-P, 786-O) and renal proximal tubule epithelial cells (RPTEC) were treated with clinically feasible concentrations of ritonavir (25-50 M) and Panobinostat (10-50 nM). Cell viability and clonogenicity were assessed by MTS assay and colony formation assay. A murine subcutaneous tumor model was used to evaluate in vivo efficacy, flow cytometry was used to detect apoptosis, and western blot analysis was used to assess the expression of HDACs and acetylated histone. Combination indexes (CI) were calculated by the Chou-Talalay method. RESULTS: The combination of ritonavir and Panobinostat induced apoptosis and inhibited cancer cell growth synergistically (CI 1). It also inhibited colony formation significantly (P 0.05). On the other hand, induction of apoptosis and cell growth inhibition were minimal in RPTEC. The combination-induced apoptosis was thought to be caspase-dependent because the pancaspase inhibitor Z-VAD-FMK reduced the number of the annexin-V positive cells produced by the combination. In murine subcutaneous tumor models using Caki-1 cells, a 10-day treatment with a combination of Panobinostat (2 mg/kg) and ritonavir (50 mg/kg) inhibited tumor growth significantly (P 0.05). Panobinostat induced histone acetylation in a dose-dependent fashion, and ritonavir enhanced this acetylation synergistically. The combination also inhibited the expression of HDACs, and this might further enhance histone acetylation. Interestingly, the combination-induced histone acetylation and apoptosis were also seen in in-vivo tumor specimens. CONCLUSIONS: Ritonavir and Panobinostat inhibited renal cancer growth synergistically by enhancing histone acetylation. The present study provides a basis for testing the combination in clinical settings.
Gary D Kao - One of the best experts on this subject based on the ideXlab platform.
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the hdac inhibitor Panobinostat lbh589 inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer
Molecular Cancer Therapeutics, 2009Co-Authors: Cecilia M Crisanti, Africa F Wallace, Veena Kapoor, Fabian Vandermeers, Melissa L Dowling, Luana Pereira, Kara Coleman, Barbara G Campling, Zvi G Fridlender, Gary D KaoAbstract:Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival pathways. We examined the efficacy of the HDACi Panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC(50) and LD(50) values were in the low nmol/L range (4-470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD(50) values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, Panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by Panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X(L). These studies together suggest that Panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC.
Cheng Wei Lin - One of the best experts on this subject based on the ideXlab platform.
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Panobinostat sensitizes KRAS-mutant non-small-cell lung cancer to gefitinib by targeting TAZ.
International journal of cancer, 2017Co-Authors: Wen Ying Lee, Pin Cyuan Chen, Chun Hsin Lan, Yen Hua Huang, Chia Hsiung Cheng, Ku Chung Chen, Cheng Wei LinAbstract:Mutation of KRAS in non-small cell lung cancer (NSCLC) shows a poor response to epidermal growth factor receptor (EGFR) inhibitors and chemotherapy. Currently, there are no direct anti-KRAS therapies available. Thus, new strategies have emerged for targeting KRAS downstream signaling. Panobinostat is a clinically available histone deacetylase inhibitor for treating myelomas and also shows potentiality in NSCLC. However, the therapeutic efficacy of Panobinostat against gefitinib-resistant NSCLC is unclear. In this study, we demonstrated that Panobinostat overcame resistance to gefitinib in KRAS-mutant/EGFR-wild type NSCLC. Combined Panobinostat and gefitinib synergistically reduced tumor growth in vitro and in vivo. Mechanistically, we identified that Panobinostat, but not gefitinib, inhibited TAZ transcription, and the combination of Panobinostat and gefitinib synergistically downregulated TAZ and TAZ downstream targets, including EGFR and EGFR ligand. Inhibition of TAZ by Panobinostat or short hairpin RNA sensitized KRAS-mutant/EGFR-wild type NSCLC to gefitinib through abrogating AKT/mammalian target of rapamycin (mTOR) signaling. Clinically, TAZ was positively correlated with EGFR signaling, and coexpression of TAZ/EGFR conferred a poorer prognosis in lung cancer patients. Our findings identify that targeting TAZ-mediated compensatory mechanism is a novel therapeutic approach to overcome gefitinib resistance in KRAS-mutant/EGFR-wild type NSCLC. This article is protected by copyright. All rights reserved.
