Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel

Abstract

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug-resistant ( Paclitaxel (Taxol**), Fig. 1, is currently used as the front-line therapeutic agent in a variety of solid forms of cancer including ovarian, breast, colon, lung, and liver neoplasms (1). Acquired resistance to paclitaxel and other commonly used cancer chemotherapy agents may be mediated by a number of mechanisms, including overexpression of the energy-dependent drug-transport protein P-glycoprotein (ref. 2, and references therein). Broad-spectrum resistance to structurally and mechanistically diverse anticancer agents constitutes the multidrugresistance (MDR) phenotype. A search for paclitaxel analogues with improved performance in vitro and in vivo has met with limited success (3, 4), although certain MDR reversal agents appear promising when coadministered with the anticancer agent (5).Although the 16-membered ring structure of the epothilones bears little structural resemblance to paclitaxel, the two agents share a common cellular mechanism of action (6-8). Both the epothilones and paclitaxel exert their biological effects by stabilizing microtubule assemblies, thus leading to the arrest of cell division and eventual cell death. By far the most intriguing property of the epothilones at the in vitro level is their lack of cross resistance to MDR cell lines when compared with major antitumor agents, including paclitaxel, vinblastine, adriamycin, camptothecin, and etoposide, all of which are currently used in clinical settings (6-9). The epothilones are also more watersoluble (6, 10-12) and more readily available through chemical synthesis (6,(13)(14)(15)(16)(17)(18)(19)(20) than is paclitaxel. The solubility advantage could allow for less cumbersome administration and increased bioavailability of the chemotherapy agent than paclitaxel. The synthetic advantage would be useful in generating epothilone congeners more advantageous than the natural product.We recently reported that Z-12,13-desoxyepothilone (dEpoB; Fig. 1), a synthetic intermediate en route to epothilone B, † † demonstrated promising activity both in vitro and in murine models harboring tumor xenografts (6, 21). In the previous report, we also showed that dEpoB was Ͼ35,000-fold more potent than paclitaxel in inhibiting cell growth of DC-3F͞ADX in vitro. During the earlier in vivo pharmacologic evaluations of the epothilones, both dEpoB and paclitaxel were administered with dimethyl sulfoxide (DMSO) as a solvent by using i.p. injection (6,22). However, i.v. administration is more appropriate for paclitaxel than for dEpoB, resulting in higher efficacy and lower toxicity. Because the primary focus of this research was to compare dEpoB and paclitaxel, we adjusted the administ...

Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal

“…However, like paclitaxel was effective in vincristine-resistant HL/ADR cells, another group of microtubule-active drugs can substitute for paclitaxel in paclitaxel-resistant HL/TX cells. In agreement with prior demonstrations that epothilones are effective against Pgp-expressing cells, 14 HL/TX cells were only marginally resistant to epothilones. Accordingly pretreatment with adriamycin, while protecting HL60 cells, did not protect either HL/ADR or HL/TX against epothilone A (data not shown) and epothilone B (Figure 6).…”

Bacterial cupredoxin azurin as an inducer of apoptosis and regression in human breast cancer

“…Hence, studies are in progress to identify pure metabolites of microbial origin or any other components of the microbial cell that might have antitumor activity. One such example is the identification of secondary metabolites, epothilones A and B of the myxobacterium Sorangium cellulosum, which have shown both in vitro and in vivo cytotoxicity in various cancer cells, including MCF-7 cells (Chou et al, 1998;Altmann et al, 2000).…”

Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy-induced apoptosis in multidrug-resistant cells but protects normal cells

“…Both MRP-and Pgp-expressing HL60 cells were still sensitive to flavopiridol (data herein), PS-341, and epothilone B. 15,22,24,25 In parental cells, caspase inhibitors B-D-fmk, Z-VAD-fmk, DEVD-fmk and Z-VEID-fmk abrogated drug-induced apoptosis. Caspase inhibitors prevented PARP cleavage, nuclear fragmentation, and sub-G1 peak on flow cytometry, and dramatically increased survival of normal cells.…”

“…It has been shown that MRP1-expressing cells were not resistant to paclitaxel (PTX); and both MRP1 and PgP-expressing cells were not resistant to epothilone B (EpoB). 22,24,25 As shown in Figure 1a, Pgp-and MRP1-expressing HL-60 cells were normally sensitive to flavopiridol with the maximal cytotoxic effect at 300 nM. Since this dose of flavopiridol kills most of the cells by 36 h (Figure 1a), it was chosen for further experiments.…”