Exploration of Molecular Targets in the Development of New Therapeutics Aimed at Overcoming Multidrug Resistance.
Multidrug resistance (MDR) in cancer is a major problem in clinical settings: MDR correlates with a patient's poor prognosis and decreased quality of life. Recently, MDR was found to be involved in various signal pathways, so the inhibition of signal molecules by molecular targeting drugs may help overcome MDR. In addition, the acquisition of MDR is shown to be associated with the overexpression of drug efflux pumps such as P-glycoprotein (MDR1), which in turn affects the regulation of the expression of cell survival factors, B-cell leukemia protein 2 (Bcl-2) family proteins, etc. We analyzed the mechanisms of MDR in hematopoietic malignancies, and showed that the activation of signaling molecules regulated the expression of drug efflux pumps and cell survival factors, thus suggesting that molecular targeting drugs are potentially useful as anti-MDR agents. In this review, I focus on recent advancements in understanding the mechanisms of MDR with respect to hematopoietic malignancies: (1) exploration of molecular targets for overcoming MDR in anti-cancer drug-resistant cell lines, (2) the mechanism of drug resistance through the cytokine autocrine loop, and (3) cell-cell interaction with bone marrow stromal cells, along with the application of molecular targeting drugs for overcoming MDR.
Laboratory of Pharmacotherapy, Faculty of Pharmacy, Kindai University.
Shozo
S
Nishida
Masanobu
M
Tsubaki
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D019898:Autocrine Communication / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D058990:Molecular Targeted Therapy / Q000639:trends; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019253:Proto-Oncogene Proteins c-bcl-2