Increased Sensitivity of the Antiestrogen-Resistant MCF-7/LY2 Human Breast Carcinoma Cell Line to Apoptosis Induced by the Novel Microtubule Stabilizing Agent (+)-Discodermolide

Abstract

(+)‐Discodermolide is a sponge‐derived natural product with the most potent microtubule stabilizing activity yet discovered. Its actions parallel that of the promising antibreast cancer agent paclitaxel despite the lack of any apparent similarities in the drugs' structures. To complement our previous studies on human breast cancer cells, we compared the effects of the two drugs against the estrogen receptor positive but tamoxifen‐resistant MCF‐7/LY2 line. Growth inhibition, cell, and nuclear morphological, electrophoretic, and flow cytometric analyses were performed. (+)‐Discodermolide potently inhibited the growth of the cells (e.g., 48‐hours IC50 of 1.5 nM) at concentrations similar to those observed with paclitaxel, and somewhat lower than the values observed previously with estrogen responsive MCF‐7 cells and estrogen nonresponsive MDA‐MB231 cells. (+)‐Discodermolide‐treated MCF‐7/LY2 cells had condensed and highly fragmented nuclei, as well as micronuclei, suggesting mitotic block and the induction of apoptosis. Flow cytometric comparison of cells treated with either drug at 10 nM showed both caused accumulation into the G2/M portion of the cell cycle as well as induction of a pronounced hypodiploid cell population, with (+)‐discodermolide yielding a greater effect. The timing and type of high molecular weight DNA fragmentation induced by the two agents was fully consistent with induction of apoptosis, again with (+)‐discodermolide showing an advantage over paclitaxel in this regard. More extensive DNA fragmentation was noted in MCF‐7/LY2 than has been observed in MCF‐7 and MDA‐MB231 cells. These in vitro results, coupled with those obtained previously, suggest that (+)‐discodermolide might have promise as a new chemotherpeutic agent against breast cancers. In addition, its novel and synthetically approachable structure make (+)‐discodermolide a promising lead compound for design and discovery of new microtubule stabilizing agents as alternatives to taxoids.

Acetylated Analogues of the Microtubule-Stabilizing Agent Discodermolide: Preparation and Biological Activity

“…The solvents were evaporated and the resulting mixture was separated by HPLC to give eight discodermolide analogues, 2-9. The high-resolution mass spectral data of the analogues in combination with the number of acetoxymethyl groups appearing in the respective 1 H NMR spectra (Tables 1 and 2) suggested the presence of one tetraacetate (2), two triacetates (3, 4), three diacetates (5, 6, 7), and two monoacetates (8,9). The number of acetoxymethyl signals and acetoxycarbonyl signals in their respective 13 C NMR spectra (Table 3) established the presence of the above four sets of acetylated analogues.…”

“…In 1990, we reported the isolation and structure determination of polypropionate-derived polyhydroxy lactone (+)-discodermolide ( 1 ) from the marine sponge Discodermia dissoluta. Subsequent studies by our group and others have indicated its immunosuppressive and antimitotic activities − with a mechanism of action similar to that of paclitaxel (Taxol): discodermolide has been shown to promote the rapid polymerization of purified tubulin and to hyperstabilize the microtubule complex in cultured cells. , (+)-Discodermolide also inhibits the in vitro growth of several cancer cell lines, including paclitaxel-resistant ovarian and colon cancer cells. − …”

“…5,6 (+)-Discodermolide also inhibits the in vitro growth of several cancer cell lines, including paclitaxel-resistant ovarian and colon cancer cells. [7][8][9] The interesting biological activity of 1 has stimulated efforts toward its total synthesis due to its low yield (0.001 to 0.002% wet wt) in the marine sponge. The Schreiber group has synthesized both antipodes, establishing the absolute configuration, 10 along with the preparation of a number of structural variants.…”

Z-1,1-Dichloro-2,3-diphenylcyclopropanes block human prostate carcinoma cell proliferation, inhibit prostate-specific antigen expression, and initiate apoptosis

“…2-(4-Methoxyphenyl)-A II caused a dose-dependent inhibition of cellular proliferation that was nearly indistinguishable in pattern between the two cell lines, yielding estimated GI 50 's of 4-6 M and GI 100 's of ∼9 M in each case (Fig. 7).…”

“…An agent that blocks PSA production could thus be useful in cases where PSA levels are indicative of prostatic hyperplasia. Because A II initiates cell cycle perturbations and apoptosis in breast cancer epithelial cells [39,49,50] and the sites of its cellular actions are potential targets for anti-CaP chemotherapy, androgensensitive LNCaP, and androgen-independent PC-3 cell lines were used in this study to investigate the potential usefulness of Z-1,1-dichloro-2,3-diphenylcyclopropanes against CaP.…”