Inhibition of Bruton's Tyrosine Kinase Suppresses Cancer Stemness and Promotes Carboplatin-induced Cytotoxicity Against Bladder Cancer Cells

2020 ◽  
Vol 40 (11) ◽  
pp. 6093-6099
Author(s):  
YUEH PAN ◽  
YA-HSU CHIU ◽  
SHAO-CHIH CHIU ◽  
DER-YANG CHO ◽  
LIANG-MING LEE ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Bruton’S Tyrosine Kinase ◽  
Cancer Stemness ◽  
Bruton's Tyrosine Kinase ◽  
Bladder Cancer Cells

scholarly journals Bruton’s Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3731
Author(s):  
Anselm Morell ◽  
Lucie Čermáková ◽  
Eva Novotná ◽  
Lenka Laštovičková ◽  
Melodie Haddad ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Anthracycline Resistance ◽  
Target Action ◽  
Combination Regimens ◽  
Btk Inhibitors

Over the last few years, aldo-keto reductase family 1 member C3 (AKR1C3) has been associated with the emergence of multidrug resistance (MDR), thereby hindering chemotherapy against cancer. In particular, impaired efficacy of the gold standards of induction therapy in acute myeloid leukaemia (AML) has been correlated with AKR1C3 expression, as this enzyme metabolises several drugs including anthracyclines. Therefore, the development of selective AKR1C3 inhibitors may help to overcome chemoresistance in clinical practice. In this regard, we demonstrated that Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib efficiently prevented daunorubicin (Dau) inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in cancer cells. This revealed a synergistic effect of BTK inhibitors on Dau cytotoxicity in cancer cells expressing AKR1C3 both exogenously and endogenously, thus reverting anthracycline resistance in vitro. These findings suggest that BTK inhibitors have a novel off-target action, which can be exploited against leukaemia through combination regimens with standard chemotherapeutics like anthracyclines.

scholarly journals Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Oncogene ◽  
2011 ◽  
Vol 31 (12) ◽  
pp. 1493-1503 ◽  
Author(s):  
A E Sayan ◽  
R Stanford ◽  
R Vickery ◽  
E Grigorenko ◽  
J Diesch ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Bladder Cancer Cells

scholarly journals Branebrutinib (BMS-986195), a Bruton’s Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents

2021 ◽  
Vol 9 ◽  
Author(s):  
Chung-Pu Wu ◽  
Megumi Murakami ◽  
Yu-Shan Wu ◽  
Ya-Chen Chi ◽  
Sung-Han Hsiao ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Kinase Inhibitor ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Bruton’S Tyrosine Kinase ◽  
Dependent Manner ◽  
Bruton's Tyrosine Kinase ◽  
P Glycoprotein ◽  
Wide Range

The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of chemotherapeutic agents out of cancer cells, thereby reducing the intracellular drug accumulation and decreasing the chemosensitivity of these multidrug-resistant cancer cells. Studies with tyrosine kinase inhibitors (TKIs) in P-gp-overexpressing cells have shown that certain TKIs could reverse MDR mediated by P-gp, while some TKIs are transported by P-gp. In the present work, we explored the prospect of repositioning branebrutinib (BMS-986195), a highly selective inhibitor of Bruton’s tyrosine kinase (BTK), to resensitize P-gp-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our results demonstrated that branebrutinib is capable of reversing P-gp-mediated MDR at sub-toxic concentrations, most likely by directly inhibiting the drug transport function of P-gp. Our findings were supported by the result of branebrutinib stimulating the ATPase activity of P-gp in a concentration-dependent manner and the in silico study of branebrutinib binding to the substrate-binding pocket of P-gp. In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies.

scholarly journals Bruton's Tyrosine Kinase Inhibitors Prevent Therapeutic Escape in Breast Cancer Cells

2016 ◽  
Vol 15 (9) ◽  
pp. 2198-2208 ◽  
Author(s):  
Xianhui Wang ◽  
Jason Wong ◽  
Christopher J. Sevinsky ◽  
Leila Kokabee ◽  
Faiza Khan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Breast Cancer Cells ◽  
Kinase Inhibitors ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase
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