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Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp.
Anticancer Res 2019; 39(7):3785-3793AR

Abstract

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.

Authors+Show Affiliations

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea syoon88@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31262905

Citation

Kim, Ji Yeong, et al. "Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp." Anticancer Research, vol. 39, no. 7, 2019, pp. 3785-3793.
Kim JY, Kim HS, Yoon S. Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp. Anticancer Res. 2019;39(7):3785-3793.
Kim, J. Y., Kim, H. S., & Yoon, S. (2019). Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp. Anticancer Research, 39(7), pp. 3785-3793. doi:10.21873/anticanres.13527.
Kim JY, Kim HS, Yoon S. Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp. Anticancer Res. 2019;39(7):3785-3793. PubMed PMID: 31262905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp. AU - Kim,Ji Yeong, AU - Kim,Hyung Sik, AU - Yoon,Sungpil, PY - 2019/04/29/received PY - 2019/06/11/revised PY - 2019/06/13/accepted PY - 2019/7/3/entrez PY - 2019/7/3/pubmed PY - 2019/7/3/medline KW - Lapatinib KW - P-gp KW - cancer KW - drug resistance KW - erlotinib KW - gefitinib KW - tyrosine kinase inhibitors SP - 3785 EP - 3793 JF - Anticancer research JO - Anticancer Res. VL - 39 IS - 7 N2 - 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. SN - 1791-7530 UR - https://www.unboundmedicine.com/medline/citation/31262905/Tyrosine_Kinase_Inhibitors_Imatinib_and_Erlotinib_Increase_Apoptosis_of_Antimitotic_Drug_resistant_KBV20C_Cells_Without_Inhibiting_P_gp_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=31262905 DB - PRIME DP - Unbound Medicine ER -