Low-Dose Rifabutin Increases Cytotoxicity in Antimitotic-Drug-Treated Resistant Cancer Cells by Exhibiting Strong P-gp-Inhibitory Activity

Abstract

The cytotoxicity of various antibiotics at low doses in drug-resistant cancer cells was evaluated. Low doses of rifabutin were found to markedly increase the cytotoxicity of various antimitotic drugs, such as vincristine (VIC), to P-glycoprotein (P-gp)-overexpressing antimitotic-drug-resistant KBV20C cells. Rifabutin was also found to exert high levels of P-gp-inhibitory activity at 4 and 24 h posttreatment, suggesting that the cytotoxicity of VIC + rifabutin was mainly due to the direct binding of rifabutin to P-gp and the reduction of VIC efflux by P-gp. The combination of VIC + rifabutin also increased early apoptosis, G2 arrest, and the DNA damaging marker, pH2AX protein. Interestingly, only the combination of VIC + rifabutin induced remarkable levels of cytotoxicity in resistant KBV20C cells, whereas other combinations (VIC + rifampin, VIC + rifapentine, and VIC + rifaximin) induced less cytotoxicity. Such finding suggests that rifabutin specifically increases the cytotoxicity of VIC in KBV20C cells, independent of the toxic effect of the ansamycin antibiotic. Only rifabutin had high P-gp-inhibitory activity, which suggests that its high P-gp-inhibitory activity led to the increased cytotoxicity of VIC + rifabutin. As rifabutin has long been used in the clinic, repositioning this drug for P-gp-overexpressing resistant cancer could increase the availability of treatments for patients with drug-resistant cancer.

Physiology‐based pharmacokinetic modelling and experimental data suggest that rifabutin alters dolutegravir kinetics by both P‐glycoprotein induction and concurrent inhibition

“…Most importantly, rifabutin potently enhanced cellular accumulation of rhodamine123, another wellknown prototypical P-gp substrate. 8 Considering the already known clinical P-gp-inhibitory effects of rifampicin (when administered simultaneously with P-gp substrate drugs such as digoxin or fexofenadine 9 ), the data presented here suggests that the in vivo consequences of rifabutin-mediated P-gp inhibition should be even higher. Noteworthy, local rifabutin concentrations in the intestine are expected to exceed 1 mM (300 mg/250 mL 10 ).…”