The effectiveness of annonaceous acetogenins against multidrug-resistant tumor cells, and, the bioactivity-directed fractionation of the unripe fruit of Persea americana
Abstract
The problem of multidrug resistance (MDR)--wherein cancer cells become resistant to structurally unrelated antineoplastic agents--was approached by investigating the hypothesis that the biochemical difference between MDR and parental cancer cells, i.e., the ATP-dependent P-glycoprotein (P-gp), results in a higher demand for ATP in the MDR cancer cells. Therefore, the acetogenins, which are biologically active natural products that have a potent ability to decrease ATP levels, were investigated for their effect on the growth of MDR cells. The adriamycin resistant (MCF-7/Adr) cell line was more susceptible than the parental human mammary adenocarcinoma (MCF-7/wt) cell line to treatment with the acetogenin bullatacin; bullatacin was cytotoxic to the MDR MCF-7/Adr cells, but it was only cytostatic to the MCF-7/wt cells. Thirteen other structurally diverse acetogenins were then subjected to the MCF-7/Adr cells to determine structure-activity relationships (SARs) in this test system. The SAR data has been normalized to that of bullatacin so that a "bullatacin index" can be used to make comparisons more easily. Persea americana Miller, Lauraceae, is cultivated for its fruit, the avocado. The roasted leaves have been used in folkloric medicine on wounds to prevent infection; a 95% ethanol extract of the leaves was the most potent of 16 plant species examined from the cloud forest of Costa Rica in the brine shrimp lethality assay (BST). From this lead, one kilo of dried unripe fruit was carried through a bioactivity directed fractionation as monitored by the BST. The three major compounds isolated were 1,2,4-trihydroxynonadecane (1), 1,2,4-trihydroxyheptadec-16-ene (2) and 1,2,4-trihydroxyheptadec-16-yne (3). 1-3 all have a 1,2,4-triol moiety and a long aliphatic chain that terminates as either an alkane, alkene, or alkyne; 1 is new while 2 and 3 have been described previously but not as anticancer agents. All have activity against six human tumor cell lines in culture and show selectivity for the human prostate adenocarcinoma (PC-3) cells with 3 being as potent as adriamycin. Also, when tested against yellow fever mosquito larva, the terminal alkyne was more potent than rotenone, a natural insecticide and positive control.
Degree
Ph.D.
Advisors
McLaughlin, Purdue University.
Subject Area
Pharmacology|Organic chemistry|Biochemistry
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