The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells
Identifieur interne : 000D91 ( Main/Exploration ); précédent : 000D90; suivant : 000D92The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells
Auteurs : Ning Wei [États-Unis] ; Edward Chu [États-Unis] ; Shao-Yu Wu [États-Unis] ; Peter Wipf [États-Unis] ; John C. Schmitz [États-Unis]Source :
- Oncotarget [ 1949-2553 ] ; 2014.
Abstract
Metastatic colorectal cancer (mCRC) remains a major public health problem, and diagnosis of metastatic disease is usually associated with poor prognosis. The multi-kinase inhibitor regorafenib was approved in 2013 in the U.S. for the treatment of mCRC patients who progressed after standard therapies. However, the clinical efficacy of regorafenib is quite limited. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may lead to synergistic enhancement of antitumor efficacy and overcome cellular drug resistance. Protein kinase D (PKD), a family of serine/threonine kinases, mediates key signaling pathways implicated in multiple cellular processes. Herein, we evaluated the combination of regorafenib with a PKD inhibitor in several human CRC cells. Using the Chou-Talalay model, the combination index values for this combination treatment demonstrated synergistic effects on inhibition of cell proliferation and clonal formation. This drug combination resulted in induction of apoptosis as determined by flow cytometry, increased PARP cleavage, and decreased activation of the anti-apoptotic protein HSP27. This combination also yielded enhanced inhibition of ERK, AKT, and NF-κB signaling. Taken together, PKD inhibition in combination with regorafenib appears to be a promising strategy for the treatment of mCRC.
Url:
PubMed: 25544765
PubMed Central: 4467112
Affiliations:
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level="a" type="main">The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells</title><author><name sortKey="Wei, Ning" sort="Wei, Ning" uniqKey="Wei N" first="Ning" last="Wei">Ning Wei</name><affiliation wicri:level="2"><nlm:aff id="A1"> Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A2"> Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Cancer Therapeutics Program, University of Pittsburgh 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Schmitz</name><affiliation wicri:level="2"><nlm:aff id="A1"> Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A2"> Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Metastatic colorectal cancer (mCRC) remains a major public health problem, and diagnosis of metastatic disease is usually associated with poor prognosis. The multi-kinase inhibitor regorafenib was approved in 2013 in the U.S. for the treatment of mCRC patients who progressed after standard therapies. However, the clinical efficacy of regorafenib is quite limited. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may lead to synergistic enhancement of antitumor efficacy and overcome cellular drug resistance. Protein kinase D (PKD), a family of serine/threonine kinases, mediates key signaling pathways implicated in multiple cellular processes. Herein, we evaluated the combination of regorafenib with a PKD inhibitor in several human CRC cells. Using the Chou-Talalay model, the combination index values for this combination treatment demonstrated synergistic effects on inhibition of cell proliferation and clonal formation. This drug combination resulted in induction of apoptosis as determined by flow cytometry, increased PARP cleavage, and decreased activation of the anti-apoptotic protein HSP27. This combination also yielded enhanced inhibition of ERK, AKT, and NF-κB signaling. Taken together, PKD inhibition in combination with regorafenib appears to be a promising strategy for the treatment of mCRC.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Siegel, R" uniqKey="Siegel R">R Siegel</name></author><author><name sortKey="Ma, J" uniqKey="Ma J">J Ma</name></author><author><name sortKey="Zou, Z" uniqKey="Zou Z">Z Zou</name></author><author><name sortKey="Jemal, A" uniqKey="Jemal A">A Jemal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kohne, Ch" uniqKey="Kohne C">CH Kohne</name></author><author><name sortKey="Lenz, Hj" uniqKey="Lenz H">HJ Lenz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chu, E" uniqKey="Chu E">E Chu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kerbel, Rs" uniqKey="Kerbel R">RS Kerbel</name></author></analytic></biblStruct><biblStruct><analytic><author><name 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uniqKey="Bergers G">G Bergers</name></author><author><name sortKey="Hanahan, D" uniqKey="Hanahan D">D Hanahan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ebos, Jm" uniqKey="Ebos J">JM Ebos</name></author><author><name sortKey="Kerbel, Rs" uniqKey="Kerbel R">RS Kerbel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meyerhardt, Ja" uniqKey="Meyerhardt J">JA Meyerhardt</name></author><author><name sortKey="Mayer, Rj" uniqKey="Mayer R">RJ Mayer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berg, M" uniqKey="Berg M">M Berg</name></author><author><name sortKey="Soreide, K" uniqKey="Soreide K">K Soreide</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vazquez, A" uniqKey="Vazquez A">A Vazquez</name></author><author><name sortKey="Bond, Ee" uniqKey="Bond E">EE Bond</name></author><author><name sortKey="Levine, Aj" uniqKey="Levine A">AJ Levine</name></author><author><name sortKey="Bond, Gl" uniqKey="Bond G">GL Bond</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Robles, Ai" uniqKey="Robles A">AI Robles</name></author><author><name sortKey="Harris, Cc" uniqKey="Harris C">CC Harris</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Wei, Ning" sort="Wei, Ning" uniqKey="Wei N" first="Ning" last="Wei">Ning Wei</name></region><name sortKey="Chu, Edward" sort="Chu, Edward" uniqKey="Chu E" first="Edward" last="Chu">Edward Chu</name><name sortKey="Chu, Edward" sort="Chu, Edward" uniqKey="Chu E" first="Edward" last="Chu">Edward Chu</name><name sortKey="Schmitz, John C" sort="Schmitz, John C" uniqKey="Schmitz J" first="John C." last="Schmitz">John C. Schmitz</name><name sortKey="Schmitz, John C" sort="Schmitz, John C" uniqKey="Schmitz J" first="John C." last="Schmitz">John C. Schmitz</name><name sortKey="Wei, Ning" sort="Wei, Ning" uniqKey="Wei N" first="Ning" last="Wei">Ning Wei</name><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name><name sortKey="Wu, Shao Yu" sort="Wu, Shao Yu" uniqKey="Wu S" first="Shao-Yu" last="Wu">Shao-Yu Wu</name><name sortKey="Wu, Shao Yu" sort="Wu, Shao Yu" uniqKey="Wu S" first="Shao-Yu" last="Wu">Shao-Yu Wu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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