Zhankuic Acids A, B and C from Taiwanofungus camphoratus Act as Cytotoxicity Enhancers by Regulating P-Glycoprotein in Multi-Drug Resistant Cancer Cells

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-In TM -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.

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…Previous reports showed that P-gp resisted apoptosis by transporting key caspases out of cells or inhibiting the activity of caspase. During apoptosis, cleavage occurs in a caspasedependent manner, which indicates the complexity of the apoptosis and MDR signaling network 100 .…”

Antrodia cinnamomea exerts an anti-hepatoma effect by targeting PI3K/AKT-mediated cell cycle progression in vitro and in vivo

“…At present, there are few studies about the relationship between zhankuic acid E and tumor. It is reported that other popular triterpenoids from A.cinnamomea plays key roles in anti-tumor, such as zhankuic acid A significantly improved the levles of G2/M arrest and sub G1 accumulation levels, trigging cell apoptosis and death of the resistant cell lines 42 , zhankuic acid A and zhankuic acid C induced cell apoptosis in colon cancer cell lines HT-29 and SW-480 43 , 44 . The ganodermanontriol significantly promoted apoptosis of Hela and HepG2 cells 45 , 46 , specifically suppressed proliferation in human breast cancer cells and colon cancer cells, and might be a potential chemotherapeutic agent for the treatment of cancer 47 , 48 .…”

Caffeic Acid Attenuates Multi-Drug Resistance in Cancer Cells by Inhibiting Efflux Function of Human P-Glycoprotein

“…The method has been described in our previous research [45]. Briefly, after 72 h of treatment of a series of concentrations of chemotherapeutic drugs with or without caffeic acid, 50% trichloroacetic acid (TCA) was added to fix cells for 30 min, and then the cells were washed with water and air-dried.…”

“…The method has been described in our previous research [45]. Cells were plated to 6-well plates with serum-free medium for starvation.…”