azadirachtin and Leukemia-P388

Four new limonoids, 1-tigloyl-3,20-diacetyl-11-methoxymeliacarpinin, 3-tigloyl-1,20-diacetyl-11-methoxymeliacarpinin, 1-cinnamoyl-3-hydroxy-11-methoxymeliacarpinin, and 1-deoxy-3-methacrylyl-11-methoxymeliacarpinin, together with a known limonoid, 1-cinnamoyl-3-acetyl-11-methoxymeliacarpinin, were isolated from the extract of the root bark of Melia azedarach. The structures were elucidated by spectroscopy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Survival; Insecticides; Leukemia P388; Limonins; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Molecular Conformation; Molecular Structure; Plant Extracts; Plant Roots; Structure-Activity Relationship; Triterpenes; Tumor Cells, Cultured

Among the compounds endowed with the capacity to reverse the P-glycoprotein (Pgp)-mediated multidrug resistance of cancer cells, a powerful agent was found to be the cyclosporin D derivative SDZ PSC 833. After in vivo treatment with SDZ PSC 833, mice showed a decreased tolerability to cyclosporin A (CsA), but also to ivermectin, a widely used polycyclic lactone pesticide of Streptomyces avermitilis origin. The sequels were suggestive of CsA- or ivermectin-induced central nervous system dysfunction; they were interpreted as caused by the neutralization of the Pgp at the blood-brain barrier level, implying that CsA and ivermectin were Pgp substrates. CsA was already known to display both Pgp substrate and Pgp inhibitor properties. It now appears that ivermectin may also inhibit Pgp function. When compared in short-term assays for Pgp function inhibition, which measure the restoration of the retention of two Pgp probes in multidrug-resistant (MDR) cells to their parental (Par) cell levels, ivermectin appeared only a few fold weaker that SDZ PSC 833 in the case of murine monocytic leukemia MDR-P388 cells and nearly as active as SDZ PSC 833 in the case of human lymphocytic leukemia MDR-CEM cells. Therefore, like CsA or FK-506, ivermectin may also be a substrate and an inhibitor of Pgp.

Topics: Animals; Antineoplastic Agents; Antiprotozoal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Ivermectin; Leukemia P388; Limonins; Mice; Triterpenes; Tumor Cells, Cultured; Vinblastine