Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal.
Drug resistance is a well recognized problem in cancer therapy. Despite the current dogma that drug resistance is always an obstacle for treatment, here I show that it provides opportunities for selective protection of non-resistant cells with killing of drug-resistant cancer cells. According to the proposed 'two-drug' strategy, the first drug should be ineffective against a target drug-resistant cell (ie the drug is a substrate of MRP or Pgp pumps). In addition, it must be cytostatic but not cytotoxic. The second drug, which is applied in sequence, must be a cycle-dependent apoptotic drug to which the target cell is not cross-resistant. Thus, low doses of adriamycin, etoposide and actinomycin D, used as the first drugs, were cytostatic to parental HL60 cells. Therefore, these drugs precluded Bcl-2/Raf-1 phosphorylation, PARP cleavage and cell death which are otherwise induced by paclitaxel, a mitosis-selective apoptotic drug for HL60 cells. In contrast, HL60/ADR cells which express MRP, a transporter which pumps out the first drugs from a cell, were insensitive to the first drugs and therefore readily underwent apoptosis following the second drug. This strategy also allowed a selective killing of HL60/TX cells which express MDR-1, with the only difference being that the second drug, paclitaxel, was substituted for epothilones, non-Pgp substrates. Lack of protection by the first drug, a Pgp substrate, resulted in HL60/TX killing by the second drug, whereas parental HL-60 cells were fully protected. Therefore, drug resistant cells can be selectively killed by a combination of drugs not killing sensitive cells. Lack of toxicity against normal cells will be clinically translated in reduction of adverse side-effects of chemotherapy against drug-resistant malignancies.
Blagosklonny
M V
MV
Medicine Branch, National Cancer Institute, Building 10, R 12N226, NIH, Bethesda, MD 20892, USA.
D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology
D004317:Doxorubicin; D017239:Paclitaxel