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.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer mortality in the U.S, and in 2014, it is expected that about 45,000 deaths will be attributed to this disease [1]
We evaluated the combination of regorafenib and Protein kinase D (PKD) inhibitors using a series of human CRC cell lines, and investigated the downstream signaling effects mediated by this combination were investigated
We evaluated the effect of regorafenib in combination with the pan-PKD inhibitor CRT0066101 on the growth of various human CRC cell lines (HCT116 p53+/+, HCT116 p53-/, RKO, HT-29, SW48 and SW48TP53 [R273H])
Summary
Colorectal cancer (CRC) is the second leading cause of cancer mortality in the U.S, and in 2014, it is expected that about 45,000 deaths will be attributed to this disease [1]. Patient tumors with high vascular density are more likely to have recurrence and metastasis [8,9,10] For this reason, the VEGF-mediated signaling pathway has served as an attractive target for drug development, and two biologic agents, bevacizumab and ziv-aflibercept, are presently approved by the U.S Food and Drug Administration (FDA) for the treatment of mCRC. Protein kinase D (PKD) is a member of the serine/ threonine kinases of the calcium/calmodulin-dependent kinase superfamily, and three main isoforms have been identified: PKD1, PKD2, and PKD3 [14] This signaling pathway plays a critical role in regulating several important cellular processes, including cell proliferation, survival, angiogenesis, DNA synthesis, adhesion, invasion/ migration, and motility [14, 15]. We evaluated the combination of regorafenib and PKD inhibitors using a series of human CRC cell lines, and investigated the downstream signaling effects mediated by this combination were investigated
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