Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells.
Through extensive screening of marine sponge compounds, the authors have found that sipholenol A, a sipholane triterpene isolated from the Red Sea sponge, Callyspongia siphonella, potently reversed multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). In experiments, sipholenol A potentiated the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine, and paclitaxel, but not the non-P-gp substrate cisplatin, and significantly reversed the MDR of cancer cells KB-C2 and KB-V1 in a concentration-dependent manner. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MDR protein 1 or breast cancer resistance protein. Sipholenol A (IC(50) > 50 microM) is not toxic to all the cell lines that were used, regardless of their membrane transporter status. Accumulation and efflux studies with the P-gp substrate [(3)H]-paclitaxel demonstrated that sipholenol A time-dependently increased the intracellular accumulation of [(3)H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. In addition, sipholenol A did not alter the expression of P-gp after treating KB-C2 and KB-V1 cells for 36 h and 72 h. However, it efficaciously stimulated the activity of ATPase of P-gp and inhibited the photolabeling of this transporter with its transport substrate [(125)I]-iodoarylazidoprazosin. Overall, the present results indicate that sipholenol A efficiently inhibits the function of P-gp through direct interactions, and sipholane triterpenes are a new class of potential reversing agents for treatment of MDR in P-gp-overexpressing tumors.
Shi
Zhi
Z
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John's University, Jamaica, NY 11439, USA.
Jain
Sandeep
S
Kim
In-Wha
IW
Peng
Xing-Xiang
XX
Abraham
Ioana
I
Youssef
Diaa T A
DT
Fu
Li-Wu
LW
El Sayed
Khalid
K
Ambudkar
Suresh V
SV
Chen
Zhe-Sheng
ZS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001386:Azides / Q000378:metabolism; D047128:Callyspongia; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D007624:KB Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019920:Photoaffinity Labels / Q000378:metabolism; D011224:Prazosin / Q000031:analogs & derivatives / Q000378:metabolism; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D001386:Azides; D007457:Iodine Radioisotopes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019920:Photoaffinity Labels; D011224:Prazosin; D014315:Triterpenes; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C523549:sipholenol A; C041552:azidoprazosin; C421109:multidrug resistance-associated protein 1