Reversal of multidrug resistance in vivo by dietary administration of the phytochemical indole-3-carbinol.
A major obstacle to successful chemotherapy is the development of multidrug resistance (MDR) by cancer cells. MDR is characterized by enhanced cellular efflux of many structurally and functionally diverse compounds, including many anticancer drugs, due to overexpression of the MDR-1 gene product, P-glycoprotein. We hypothesized that the phytochemical, indole-3-carbinol (I3C), and some of its acid-condensation derivatives may inhibit P-glycoprotein-mediated transport due to their aromatic and nitrogen components, thus increasing the accumulation and efficacy of anticancer drugs and acting as a dietary adjuvant to conventional chemotherapy. I3C was subjected to acid conditions similar to those occurring in the stomach following ingestion and three acid-condensation products; a dimer, a noncyclic trimer, and a cyclic trimer were isolated and purified by high-performance liquid chromatography. The ability of I3C and its acid-condensation derivatives to reverse MDR was investigated using murine B16 melanoma cells that were transfected with the human MDR-1 gene (B16/hMDR-1 cells) and were cross-resistant to vinblastine and doxorubicin. The I3C acid-condensation product mixture, but not I3C, sensitized B16/hMDR-1 transfectants to the toxicity of vinblastine and doxorubicin. All three I3C acid-condensation products also increased the accumulation of the P-glycoprotein substrate, doxorubicin, in B16/hMDR-1 transfectants to levels comparable to parental B16 cells. The I3C acid-condensation product mixture competed with azidopine for binding to P-glycoprotein, suggesting that the observed MDR-reversing effect of the acid-condensation products was due to direct interaction with P-glycoprotein. The ability of p.o. administered I3C to reverse MDR was also tested in vivo. The resistance of B16/hMDR-1 transfectants to vinblastine and doxorubicin was preserved after i.p. injection and growth in nude mice. Tumor mass in mice that were provided with 333 or 500 mg/kg mouse/day I3C in their diet and injected s.c. with the anticancer drugs doxorubicin or vinblastine was significantly reduced as compared to tumor mass in mice provided with standard diet and injected with these anticancer drugs or mice provided with 500 mg/kg mouse/day I3C and not injected with anticancer compound. The concentrations of I3C used had no effect on survival or the general appearance and behavior of the mice. Collectively, these results indicate that ingestion of the common dietary constituent I3C results in its conversion to acid-condensation derivatives that sensitized MDR tumors to chemotherapeutic drugs without eliciting direct toxicity to the host.
Christensen
J G
JG
Department of Toxicology, North Carolina State University, Raleigh 27695-7633, USA.
LeBlanc
G A
GA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001386:Azides / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010641:Phenotype; D014162:Transfection; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D007211:Indoles; D014316:Tritium; C041130:azidopine; D004317:Doxorubicin; C016517:indole-3-carbinol