4-hydroxy-25-desoxyneorollinicin and Adenocarcinoma

To explore the effect of atemoyacin-B (Ate) on overcoming multidrug resistance (MDR).. Bullatacin (Bul) was used as a positive control. Cytotoxic effects of Bul and Ate were studied with cell culture of human MDR breast adenocarcinoma cells, MCF-7/Dox and human KBv200 cells, and their parental sensitive cell lines MCF-7 and KB. Cytotoxicity was determined by tetrazolium (MTT) assay. The function of P-glycoprotein (P-gp) was examined by Fura 2-AM assay. Cellular accumulation of doxorubicin (Dox) was determined by fluorescence spectrophotometry. Apoptosis was measured by flow cytometry.. IC50 of Ate for MCF-7/Dox, MCF-7, KBv200, and KB cells were 122, 120, 1.34, and 1.27 nmol.L-1, respectively. IC50 of Bul for MCF-7/Dox, MCF-7, KBv200, and KB cells were 0.60, 0.59, 0.04, and 0.04 nmol.L-1, respectively. The cytotoxicities of Bul and Ate to MDR cells were similar to those to parental sensitive cells. Bul and Ate markedly increased cellular Fura-2 and Dox accumulation in MCF-7/Dox cells, but not in MCF-7 cells. The rates of apoptosis in MDR cells were similar to those in sensitive cells induced by Ate.. There was no cross-resistance of P-gp positive MCF-7/Dox and KBv200 cell lines to Bul and Ate as compared with their sensitive P-gp negative MCF-7 and KB cell lines. The mechanism of the circumvention of MDR was associated with the decrease of P-gp function and the increase of cellular drug accumulation in MDR cells.

Topics: 4-Butyrolactone; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fatty Alcohols; Fura-2; Furans; Humans; KB Cells; Tumor Cells, Cultured

Cytotoxic effects of the Annonaceous acetogenin, bullatacin, were studied in multidrug-resistant (MDR) human mammary adenocarcinoma (MCF-7/Adr) cells vs. the parental non-resistant wild type (MCF-7/wt) cells. Bullatacin was effectively cytotoxic to the MCF-7/Adr cells while it was more cytostatic to the MCF-7/wt cells. ATP depletion is the mode of action of the Annonaceous acetogenins, and these agents offer a special advantage in the chemotherapeutic treatment of MDR tumors that have ATP-dependent mechanisms.

Topics: Adenocarcinoma; Adenosine Triphosphate; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Division; Drug Resistance, Multiple; Furans; Humans; Tumor Cells, Cultured

Fourteen structurally diverse Annonaceous acetogenins, representing the three main classes of bis-adjacent, bis-nonadjacent, and single-THF ring(s), were tested for their ability to inhibit the growth of adriamycin resistant human mammary adenocarcinoma (MCF-7/Adr) cells. This cell line is resistant to treatment with adriamycin, vincristine, and vinblastine and is, thus, multidrug resistant (MDR). Among a series of bis-adjacent THF ring acetogenins, those with the stereochemistry of threo-trans-threo-trans-erythro (from C-15 to C-24) were the most potent with as much as 250 times the potency of adriamycin. A spacing of 13 carbons between the flanking hydroxyl of the THF ring system and the gamma-unsaturated lactone seems to be optimum with a spacing of 11 and 9 carbons being significantly less active. Several single-THF ring compounds were also quite potent with gigantetrocin A (11) being the most potent compound tested. The acetogenins may, thus, have chemotherapeutic potential, especially with regard to MDR tumors.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Furans; Humans; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured