sdz-psc-833 and Carcinoma--Non-Small-Cell-Lung

A new polyoxypregnane aglycone, tenacigenin D (1), and seven new C21 steroid glycosides, tenacissimosides D-J (2-8), were isolated from the stems of Marsdenia tenacissima. Their structures were determined by interpretation of their 1D and 2D NMR and other spectroscopic data, as well as by comparison with published values for related known compounds. Compound 1 was found to circumvent P-glycoprotein (P-gp)-mediated multidrug resistance through an inhibitory effect on P-gp with a similar potency to verapamil. In addition, compound 1 potentiated the activity of erlotinib and gefitinib in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)-resistant non-small-cell lung cancer cells.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Gefitinib; Glycosides; Humans; Marsdenia; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pregnanes; Quinazolines

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Cyclosporins; Dibenzocycloheptenes; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Investigational; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; National Institutes of Health (U.S.); Neoplasms; Piperidines; Pyridines; Quinolines; United States

The doxorubicin-selected multidrug resistant (MDR) human large cell lung cancer line COR-L23/R, lacks P-glycoprotein but shows a drug accumulation deficit. It does however overexpress a 190k membrane protein which shares an epitope with, but is otherwise distinct from, P-glycoprotein. The resistant cells show only a small sensitisation to vincristine and daunorubicin on treatment with cyclosporin A and its more potent analogue, PSC-833 despite an increase in drug accumulation. Verapamil, another effective resistance modifier in P-glycoprotein MDR cells, is slightly more effective. Fluorescent daunorubicin distributes in the cytoplasm and nucleus of sensitive parent COR-L23 cells but is confined to cytoplasmic perinuclear vesicles in resistant cells. Addition of cyclosporin A or PSC-833 slightly increases cytoplasmic fluorescence whereas verapamil also increases nuclear fluorescence. Resistance in this non-P-glycoprotein MDR line, COR-L23/R where these resistance modifiers have little effect may be associated with expression of the 190k protein.

Topics: Carcinoma, Non-Small-Cell Lung; Cyclosporine; Cyclosporins; Daunorubicin; Humans; Lung Neoplasms; Membrane Proteins; Molecular Weight; Neoplasm Proteins; Tumor Cells, Cultured; Verapamil; Vincristine