Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of reserpine and a possible mechanism by which it reverses the resistance to both doxorubicin and pirarubicin in doxorubicin-resistant P388 leukemia (P388/DOX) cells were examined in vitro. During 48 hr drug-exposure, the sensitivity of doxorubicin and pirarubicin were potentiated markedly when reserpine was present at the concentration of 1 microgram/ml, which is not toxic to P388 leukemia (P388/S) cells. However, reserpine had little effect on the cytotoxicity of doxorubicin and pirarubicin in the sensitive parent cell. Reserpine at 0.5-20 micrograms/ml increased intracellular accumulation of doxorubicin and pirarubicin in the drug-resistant cells. The potentiating action of reserpine was stronger when the cells were preincubated with reserpine within 30 min. Efflux of doxorubicin and pirarubicin was greater in drug-resistant cells compared to sensitive cells. This enhanced efflux of drug resulted in a decrease in the intracellular accumulation of doxorubicin in the drug-resistant cells. When the resistant cells were exposed to 2 micrograms/ml of reserpine, this enhanced efflux was blocked. A similar effect of reserpine on doxorubicin was seen with the efflux pattern of pirarubicin. From the measurements of drug uptake and efflux, it seems that like other multiple drug resistance modifiers, reserpine modulates anthracycline resistance by increasing intracellular accumulation of drug.
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PMID:[Modulation of anthracycline resistance by reserpine in P388 leukemia cells]. 188 60

We have shown previously that reserpine is an effective "modulator" of P-glycoprotein-associated multidrug resistance (MDR). In addition to enhancing drug cytotoxicity in our multidrug-resistant human leukemia cell line, CEM/VLB100, reserpine strongly competes with a photoactivatible analog of vinblastine, N-(p-azido-3-[125I]iodosalicyl)-N'-(beta-aminoethyl)vindesine, for binding to P-glycoprotein. We also demonstrated previously that there are three substructural domains present in many compounds that modulate P-glycoprotein-associated MDR: a basic nitrogen atom and two planar aromatic rings. In the present study, we wished to test more rigorously the hypothesis that not only are these domains necessary for modulators of MDR but also they must exist in an appropriate conformation. Reserpine is a modulator of MDR in which these domains are present in a well-defined conformation. Accordingly, we prepared eight compounds that vary the spatial orientation of these domains, using either naturally occurring reserpine or yohimbine as chemical templates. When tested for their ability to enhance the cytotoxic activity of natural product antitumor drugs in CEM/VLB100 cells, five compounds that retained the pendant benzoyl function in an appropriate spatial orientation all modulated MDR. By contrast, compounds lacking this moiety failed to do so. These active modulators competed strongly with the 125I-labeled vinblastine analog for binding to P-glycoprotein in plasma membrane vesicles prepared from these cells. Conformational analysis using molecular mechanics revealed the structural similarities of the active modulators. Our results support the hypothesis that the relative disposition of aromatic rings and basic nitrogen atom is important for modulators of P-glycoprotein-associated MDR, and they suggest a ligand-receptor relationship for these agents. These results also provide direction for the definition of an MDR "pharmacophore."
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PMID:Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance. 256 94

Reserpine, the crystalline active substance isolated from the Rauvolfia plant, produces a characteristic vasodepressor effect in hypertensive patients. Apart from its antihypertensive property, reserpine also possesses transquillising and vasodepressor action, hence it is employed as supportive therapy in the treatment of cardiac disorders. Doxorubicin is a potent anticancer agent, the use of which is limited by its cumulative dose-dependent cardiotoxicity. Epirubicin is a derivative of doxorubicin having more favourable therapeutic index than doxorubicin and possessing less hematologic and cardiac toxicity at comparable doses. The data presented in this paper show the effect of reserpine as a chemosensitizer, when used in combination with epirubicin on P388 murine leukemia cells sensitive (P388/S) and resistant to doxorubicin (P388/DOX) cells. Inhibition of 3H-TdR incorporation into DNA was used as an index of the cytotoxic effects of drug when used alone or in combination. The combination of reserpine (1 microM) and epirubicin (1.7, 8.6 and 17.2 microM) indicated a significant enhancement in the DNA biosynthesis inhibition in P388/S and P388/DOX cell lines. The most prominent feature of the multidrug-resistant cell is the reduced accumulation of the drug intracellularly. P388/DOX cells showed less accumulation of epirubicin in the cell as compared to that of the parental cell line. Further studies demonstrated that reserpine significantly enhanced the intracellular accumulation of epirubicin in both the cell lines. The nature of DNA damage caused by the combination of reserpine and epirubicin was irreversible when studied in P388/DOX cell line. The combination of reserpine (5mg/kg) and epirubicin (1mg/kg) significantly potentiated the antitumor activity of epirubicin in P388/DOX tumor bearing mice. These studies suggest that reserpine can be used as an adjuvant in the cancer chemotherapy to potentiate the antiproliferative activity of anticancer drugs.
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PMID:Sensitization of P388 murine leukemia cells to epirubicin cytotoxicity by reserpine. 781 52