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      Low-Dose Crizotinib, a Tyrosine Kinase Inhibitor, Highly and Specifically Sensitizes P-Glycoprotein-Overexpressing Chemoresistant Cancer Cells Through Induction of Late Apoptosis in vivo and in vitro


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          We investigated possible conditions or drugs that could target P-glycoprotein (P-gp)-overexpressing drug-resistant KBV20C cancer cells. Specifically, we focused on identifying a single treatment with a relatively low half maximal inhibitory concentration (IC 50). Our approach utilized repurposing drugs, which are already used in clinical practice. We evaluated 13 TKIs (gefitinib, imatinib, erlotinib, nilotinib, pazopanib, masatinib, sunitinib, sorafenib, regorafenib, lapatinib, vandetanib, cediranib, and crizotinib) for their sensitizing effects on P-gp-overexpressing drug-resistant KBV20C cells. We found that crizotinib had a much greater sensitization effect than the other tested drugs at relatively low doses. In a detailed quantitative analysis using both lower doses and time-duration treatments, we demonstrated that crizotinib, which increased the levels of apoptosis and G2 arrest, was the best TKI to induce sensitization in P-gp-overexpressing KBV20C cells. Upon comparing resistant KBV20C cells and sensitive KB parent cells, crizotinib was found to markedly sensitize drug-resistant KBV20C cancer cells compared with other TKIs. This suggests that crizotinib is a resistant cancer cell-sensitizing drug that induces apoptosis. In mice bearing xenografted P-gp-overexpressing KBV20C cells, we confirmed that crizotinib significantly reduced tumor growth and weight, without apparent side effects. In addition, although lapatinib and crizotinib have a high P-gp inhibitory activity, we found that co-treatment with crizotinib and vincristine (VIC) did not have much of a sensitization effect on KBV20C cells, whereas lapatinib had a high sensitization effect on VIC-treated KBV20C cells. This suggests that crizotinib is a single-treatment specific drug for resistant cancer cells. These findings provide valuable information regarding the sensitization of drug-resistant cells and indicate that low-dose crizotinib monotherapy may be used in patients with specific P-gp-overexpressing chemoresistant cancer.

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          Most cited references43

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          An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.

          The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.
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            Taxanes, microtubules and chemoresistant breast cancer.

            The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment.
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              Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.

              Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                12 May 2020
                : 10
                : 696
                School of Pharmacy, Sungkyunkwan University , Suwon-si, South Korea
                Author notes

                Edited by: Olivier Feron, Université Catholique de Louvain, Belgium

                Reviewed by: Andaleeb Sajid, Yale University, United States; Zhe-Sheng Chen, St. John's University, United States

                *Correspondence: Hyung Sik Kim hkims@ 123456skku.edu

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology

                Copyright © 2020 Kim, Jiang, Kim, Park, Kim, Lee, Kim and Yoon.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 04 December 2019
                : 14 April 2020
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 52, Pages: 12, Words: 8497
                Original Research

                Oncology & Radiotherapy
                crizotinib,monotherapy,single treatment,tyrosine kinase inhibitors,cancer,p-gp,drug-resistance


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