Ribociclib Inhibits P-gp-Mediated Multidrug Resistance in Human Epidermoid Carcinoma Cells

Abstract

The efficacy of cancer chemotherapy can be attenuated or abrogated by multidrug resistance (MDR) in cancer cells. In this study, we determined the effect of the CDK4/6 inhibitor, ribociclib (or LEE011), on P-glycoprotein (P-gp)-mediated MDR in the human epidermoid carcinoma MDR cell line, KB-C2, which is widely used for studying P-gp-mediated MDR in cancers. The incubation of KB-C2 cells with ribociclib (3–9 µM) increased the efficacy of colchicine, a substrate for P-gp. The cell expression of P-gp was down-regulated at both translation and transcription levels. Furthermore, ribociclib produced a 3.5-fold increase in the basal activity of P-gp ATPase, and the concentration required to increase basal activity by 50% (EC50) was 0.04 μM. Docking studies indicated that ribociclib interacted with the drug-substrate binding site of P-gp. The short-term and long-term intracellular accumulation of doxorubicin greatly increased in the KB-C2 cells co-cultured with ribociclib, indicating ribociclib inhibited the drug efflux activity of P-gp. The results of our study indicate that LEE011 may be a potential agent for combined therapy of the cancers with P-gp mediated MDR.

Potential Pharmacokinetic Effect of Chicken Xenobiotic Receptor Activator on Sulfadiazine: Involvement of P-glycoprotein Induction

“…P-gp protects the healthy body from foreign substances, but it has also become a major obstacle to disease treatment by restricting drug delivery to tissues. P-gp has attracted growing research efforts directed at its involvement in drug disposition (absorption, distribution and elimination) and DDIs [ 23 ]. Combined administration of drugs that inhibit or induce P-gp may increase or reduce systemic exposure to P-gp substrates, respectively [ 24 ].…”

Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

“…It is quite easy to achieve anti-tumor reagents such as inhibitors, however, as to how to improve the properties of these reagents as drugs, their biological availability, half-life, biocompatibility, and so on, are highly concerned as common issues that might make them more efficient and less harmful to the patients during clinical applications. Till now, hundreds of studies surrounding clinical application of the anti-tumor drugs for curation of MDR cancers, or those focusing on the anti-tumor drug systems with high potential for clinical translation have been published 1 , 5 , 11 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 .…”

“…The emergence of multidrug resistance (MDR) is one main reason for the failure of cancer chemotherapy 1 , 2 , 3 . The MDR cancer cells exhibit cross-resistance to a broad spectrum of structurally unrelated drugs 2 .…”

Mechanism of multidrug resistance to chemotherapy mediated by P‑glycoprotein (Review)

“…Small molecule targeted drugs branebrutinib ( 66 ), pyrazolo[3,4-d]pyrimidines ( 67 ), almonertinib ( 68 ) and ribociclib ( 69 ) may be potential inhibitors of P-gp. They can compete with P-gp while exerting their own tumor-killing effects, thereby improving chemotherapy sensitivity.…”

“…A novel platinum complex can also effectively alleviate cisplatin resistance by inhibiting the expression of P-gp ( 115 ). Ribociclib, a CDK4/6 inhibitor, inhibits P-gp-mediated DOX resistance by downregulating the expression and efflux activity of P-gp ( 69 ). The small molecule targeted inhibitors sorafenib and apatinib also inhibit P-gp expression and MDR while inducing anticancer effects ( 116 ).…”