Abstract
Since P-glycoprotein (P-gp)-related multidrug resistance (MDR) remains the most important unsolved problem in cancer treatment, scientists are attempting to find potential structures from natural resources. The aim of the present study was to elucidate whether the triterpenoids from Taiwanofungus camphoratus could reverse cancer MDR by influencing P-gp efflux pump. Substrates efflux assay and P-gp ATPase activity assay were conducted to reveal the molecular mechanisms of P-gp inhibition, while SRB assay, cell cycle analyses and apoptosis analyses were performed to confirm the cancer MDR modulating effects. The results indicated that Zhankuic acids A, B and C (ZA-A, ZA-B and ZA-C) impacted P-gp efflux function in competitive, noncompetitive and competitive manners, respectively. Furthermore, these triterpenoids all demonstrated inhibitory patterns on both basal P-gp ATPase activity and verapamil-stimulated ATPase activity. In terms of MDR reversal effects, ZA-A sensitized the P-gp over-expressing cell line (ABCB1/Flp-InTM-293) and MDR cancer cell line (KB/VIN) toward clinically used chemotherapeutic drugs, including doxorubicin, paclitaxel and vincristine, exhibiting the best cytotoxicity enhancing ability among investigated triterpenoids. The present study demonstrated that ZA-A, ZA-B and ZA-C, popular triterpenoids from T. camphoratus, effectively modulated the drug efflux transporter P-gp and reversed the cancer MDR issue.
Highlights
Despite ever-advancing science and technology in medical treatment, the cancer mortality rate remains the highest among numerous human diseases
The present study demonstrated that Zhankuic acids A (ZA-A), ZA-B and ZA-C, popular triterpenoids from T. camphoratus, effectively modulated the drug efflux transporter P-gp and reversed the cancer multidrug resistance (MDR) issue
P-gp Efflux Function was Inhibited by ZA-A, ZA-B and ZA-C
Summary
Despite ever-advancing science and technology in medical treatment, the cancer mortality rate remains the highest among numerous human diseases. Combinatorial chemotherapy addresses the resistance caused by single drug treatment; the ensuing side effects and multidrug resistance. Several molecular mechanisms of resistance have been identified, including interrupted cellular apoptotic pathways, enhanced DNA damage repair and insufficient chemotherapeutic drug concentrations in cancer cells caused by reduced drug intake or increased drug efflux [2]. In cancer MDR, the overexpression of drug efflux transporter P-glycoprotein (P-gp) has been a major concern over the past 40 years [3]. P-gp can recognize and pump out numerous hydrophobic drugs, including chemotherapeutic agents, by changing its conformation under ATP consumption [4]
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