Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells

Manohar, Sonal M; Padgaonkar, Amol; Jalota‐Badhwar, Archana; Rao, Shalini; Joshi, Kavita

doi:10.1038/pcan.2011.51

Cited by 19 publications

(15 citation statements)

References 35 publications

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“…P276-00, a cyclin-dependent kinase inhibitor, inhibits HIF-1a and induces G2/M arrest under hypoxia in prostate cancer cells. 31 Some studies have reported that ERK-or JNK/MAPK activation induces G2/M phase arrest and apoptosis in solid tumors. [32][33][34][35][36] We found that palbociclib destabilizes HIF-1a and activates ERK1/2 under either normoxic or hypoxic conditions (Fig.…”

Section: Discussionmentioning

confidence: 99%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1a regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3b. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1a accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3b signaling and GSK-3b expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1a accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.

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Section: Discussionmentioning

confidence: 99%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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“…Some chemicals such as Acriflavine and Digoxin have been developed to inhibit HIF-1 dimerization and synthesis, thereby blocking tumor growth and vascularization [200,201]. Furthermore, P276-00, a cyclin-dependent kinase inhibitor, has been shown to inhibit HIF-1α transcription and induce G2/M cell cycle arrest in prostate cancer cells under hypoxic conditions [202,203]. Finally, trichostatin A (TSA) has proven to degrade HIF-1α by inhibiting histone deacetylases [204].…”

Section: Implications For Cancer Therapy and Chemopreventionmentioning

confidence: 99%

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

Justus

Sanderlin

Yang

2015

IJMS

116

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Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention.

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“…The in vitro cellular potency, together with in vivo antitumor activity has been demonstrated for multiple myelomas (10). The mechanism of inhibition in multiple myoloma cells was determined to be through inhibition of cdk9 and RNA polymerase II dependent transcription (11, 12). P276 has also been demonstrated to inhibit transcriptional activation of HIF-1 and phosphorylation of Akt and 4E-BP1 in prostate cancer cells (12).…”

Section: Introductionmentioning

confidence: 99%

CDK-4 Inhibitor P276 Sensitizes Pancreatic Cancer Cells to Gemcitabine-Induced Apoptosis

Subramaniam

Periyasamy²,

Ponnurangam³

et al. 2012

Molecular Cancer Therapeutics

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Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine (Gem) is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G2/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to Gem induced apoptosis, a mechanism mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and Gem resulted in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase 3 and increased Bax/Bcl2 ratio. Gene profiling studies demonstrated that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by western blot analyses. There was also a downregulation of vascular endothelial growth factor (VEGF) and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31 positive blood vessels, and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis.

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Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells

Cited by 19 publications

References 35 publications

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

CDK-4 Inhibitor P276 Sensitizes Pancreatic Cancer Cells to Gemcitabine-Induced Apoptosis

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