Modulation of P-glycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol.
Resistance to chemotherapeutic drugs is one of the major problems in the treatment of cancer. P-glycoprotein (P-gp) encoded by the mdr gene is a highly conserved protein, acts as a multidrug transporter, and has a major role in multiple drug resistance (MDR). Targeting of P-gp by naturally occurring compounds is an effective strategy to overcome MDR. Indole-3-carbinol (I3C), a glucosinolates present in cruciferous vegetables, is a promising chemopreventive agent as it is reported to possess antimutagenic, antitumorigenic, and antiestrogenic properties in experimental studies. In the present investigation, the potential of I3C to modulate P-gp expression was evaluated in vinblastine (VBL)-resistant K562 human leukemic cells. The resistant K562 cells (K562/R10) were found to be cross-resistant to vincristine (VCR), doxorubicin (DXR), and other antineoplastic agents. I3C at a nontoxic dose (10 x 10(-3) M) enhanced the cytotoxic effects of VBL time dependently in VBL-resistant human leukemia (K562/R10) cells but had no effect on parent-sensitive cells (K562/S). The Western blot analysis of K 562/R 10 cells showed that I3C downregulates the induced levels of P-gp in resistant cells near to normal levels. The quantitation of immunocytochemically stained K562/R10 cells showed 24%, 48%, and 80% decrease in the levels of P-gp by I3C for 24, 48, and 72 h of incubation. The above features thus indicate that I3C could be used as a novel modulator of P-gp-mediated multidrug resistance in vitro and may be effective as a dietary adjuvant in the treatment of MDR cancers.
Arora
Annu
A
Environmental Carcinogenesis Division, Industrial Toxicology Research Centre, M.G. Marg, Lucknow-226001, India.
Seth
Kavita
K
Kalra
Neetu
N
Shukla
Yogeshwer
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D004317:Doxorubicin; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014700:Verapamil; D014747:Vinblastine; D014750:Vincristine; C016517:indole-3-carbinol