Multidrug Resistance Protein 2 Implicates Anticancer Drug-Resistance to Sorafenib

Shibayama, Yoshihiko; Nakano, Kou; Maeda, Hiroshi; Taguchi, Miyuki; Ikeda, Ryuji; Sugawara, Mitsuru; Iseki, Ken; Takeda, Yasuo; Yamada, Katsushi

doi:10.1248/bpb.34.433

Cited by 52 publications

(43 citation statements)

References 16 publications

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“…In addition to the above described mechanisms, some limited studies have also demonstrated that EGFR [10] , glucose-regulated protein 78 (GRP78) [41] , multidrug resistance protein (MDRP) 2 [42] , nuclear factor κB (NF-κB) [43,44] and autophagy [45] may be involved in the acquired resistance to sorafenib in HCC.…”

Section: Hypoxic Microenvironment and Sorafenib Resistancementioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

163

152

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Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. Core tip: The primary resistance of hepatocellular carcinoma (HCC) to sorafenib is due to genetic heterogeneity. Thus, seeking predictive biomarkers and combining sorafenib with other anticancer agents for HCC have been launched with varying degrees of success. Sorafenib inhibits several kinase targets but it can also simultaneously or sequentially activate the addiction switches and compensatory pathways, inducing acquired resistance. Some other molecular targeted drugs have been used as second-line treatment for advanced HCC after the failure of sorafenib therapy. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms accounting for sorafenib resistance in HCC.Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5(7): 345-352 Available from:

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Section: Hypoxic Microenvironment and Sorafenib Resistancementioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

163

152

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“…The two inhibitors show significant activity against neovascularization-related RTKs, such as VEGFR2, VEGFR3, and PDGFR-β (23,24). Although one of the most noteworthy target kinases of sorafenib is Raf-1, the contribution of the Raf kinase inhibitory properties of sorafenib to the antitumor effect in RCC is not completely understood (1).…”

Section: A B C D Ementioning

confidence: 99%

“…One of the main causes of the MDR phenotype is the overexpression of P-glycoprotein, encoded by the multidrug resistance gene (MDR1) and multidrug resistance-associated proteins (MRP) (23). Findings of a recent study have shown that of the two MKIs, only sorafenib is a substrate for MRP2, a clinically significant member of the MRP transporter family (24). In addition, MRP2 is known to be linked to resistance against 5FU (25).…”

Section: A B C D Ementioning

confidence: 99%

5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma

et al. 2012

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“…25 The cellular efflux mechanisms of sorafenib and nilotinib have been reported in various studies and involved breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and multidrug resistance protein (MRP)-2 for sorafenib only. [60][61][62][63] Interestingly, while there is no basal expression of P-gp reported in these cell lines, treatment with a chemotherapeutic agent may induce …”

mentioning

confidence: 91%

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

Archibald

Pritchard

Nehoff

et al. 2016

IJN

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Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene- co -maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing.

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Multidrug Resistance Protein 2 Implicates Anticancer Drug-Resistance to Sorafenib

Cited by 52 publications

References 16 publications

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

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