PT  - JOURNAL ARTICLE
AU  - JI YEONG KIM
AU  - HYUNG SIK KIM
AU  - SUNGPIL YOON
TI  - Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp
AID  - 10.21873/anticanres.13527
DP  - 2019 Jul 01
TA  - Anticancer Research
PG  - 3785--3793
VI  - 39
IP  - 7
4099  - http://ar.iiarjournals.org/content/39/7/3785.short
4100  - http://ar.iiarjournals.org/content/39/7/3785.full
SO  - Anticancer Res2019 Jul 01; 39
AB  - Background/Aim: This study investigated drugs able to sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to vincristine or eribulin treatment and assessed their associated mechanisms of action. Materials and Methods: Eight tyrosine kinase inhibitors (lapatinib, gefitinib, imatinib, erlotinib, nilotinib, pazopanib, cediranib, and vandetanib) and one serine/threonine kinase inhibitor (selumetinib) were evaluated for their sensitizing effects on vincristine-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were further performed to investigate their mechanisms of action. Results: Co-treatment of KBV20C cells with lapatinib, gefitinib, imatinib, or erlotinib at low doses highly sensitized them to vincristine treatment. These drugs reduced cellular viability, increased G2 arrest, and up-regulated apoptosis when co-administered with vincristine. In a detailed quantitative analysis using lower doses, we demonstrated that lapatinib, with high P-gp inhibitory activity, yielded the best pairing for sensitizing P-gp-overexpressing KBV20C cells to vincristine. Co-treatment with eribulin and lapatinib, gefitinib, or erlotinib also increased the sensitivity of KBV20C cells, suggesting that they can be combined with other antimitotic drugs to sensitize resistant cancer cells. Lapatinib was shown to have a higher P-gp-inhibitory activity than verapamil, even at lower doses, indicating that its sensitizing of cells to vincristine involves its P-gp-inhibitory effects. However, interestingly, imatinib- and erlotinib-sensitizing of cells to vincristine appears to be independent of their P-gp inhibition. Conclusion: These findings provide valuable information regarding the sensitizing of drug-resistant cells and indicate that imatinib and erlotinib may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.