Abstract
Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells. Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et al., Clin. Cancer Res., 6: 1978-1987, 2000). To understand their synergy, we examined the effects of the two drugs singly and in combination in A549 cells and found that, surprisingly, their antiproliferative synergy is related to their ability to synergistically inhibit microtubule dynamic instability and mitosis. The combination of discodermolide and paclitaxel at their antiproliferative IC(50)s (7 nm for discodermolide and 2 nm for paclitaxel) altered all of the parameters of dynamic instability synergistically except the time-based rescue frequency. For example, together the drugs inhibited overall microtubule dynamicity by 71%, but each drug individually inhibited dynamicity by only 24%, giving a combination index (CI) of 0.23. Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G(2)-M (41, 9.6, and 16% for both drugs together, for discodermolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85). Microtubules are unique receptors for drugs. The results suggest that ligands that bind to large numbers of binding sites on an individual microtubule can interact in a poorly understood manner to synergistically suppress microtubule dynamic instability and inhibit both mitosis and cell proliferation, with important consequences for combination clinical therapy with microtubule-targeted drugs.
Highlights
Lones or eleutherobin did not inhibit cell proliferation synergistically [8]
We examined the effects of the two drugs singly and in combination on microtubule dynamic instability in living A549 human lung cancer cells during interphase at drug concentrations that inhibited proliferation
To determine the concentrations of discodermolide and paclitaxel to use to examine their potential synergistic actions on microtubule dynamics, we first determined the effects of the two drugs individually on cell proliferation and mitotic arrest in A549 cells over a range of drug concentrations
Summary
Lones or eleutherobin (drugs that bind to the paclitaxel binding site) did not inhibit cell proliferation synergistically [8]. Because discodermolide and paclitaxel both suppress microtubule dynamics at concentrations that disrupt mitosis and inhibit cell proliferation, we asked whether the synergistic antiproliferative actions of discodermolide and paclitaxel that have been observed in tumor cells might result from synergism in their effects on microtubule dynamic instability. Discodermolide increases microtubule polymer mass and induces cold- and calciumstable tubulin polymers [1, 2] In cells, it induces microtubule bundling, cell cycle arrest at the G2-M phase, aneuploidy, and apoptosis [1,2,3,4]. The results have important consequences for clinical therapy with combinations of drugs that bind to the same or overlapping sites on microtubules
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