Epothilones: Mechanism of Action and Biologic Activity

Goodin, Susan; Kane, Michael P.; Rubin, Eric H.

doi:10.1200/jco.2004.12.001

Cited by 310 publications

(183 citation statements)

References 34 publications

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“…Epothilones have been reported to trigger apoptotic cell death in several cancer cell lines in vitro and to inhibit tumor cell growth in vivo (2,3). Like paclitaxel (Taxol), epothilones have been reported to block the cell cycle at G 2 -M and to subsequently induce apoptotic cell death in several cancer cells (2,4). However, the biochemical mechanisms that underlie epothiloneinduced cancer cell growth inhibition are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway

Lee

Son²,

Son³

et al. 2007

Molecular Cancer Therapeutics

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Molecular mechanisms underlying epothilone-induced apoptotic cell death were investigated in SW620 human colon cancer cells. Treatment with epothilone B and D at different concentrations (1-100 nmol/L) dose-dependently inhibited cell growth and caused cell cycle arrest at G 2 -M, which was followed by apoptosis. Consistent with this induction of apoptotic cell death, epothilone B and D enhanced the constitutional activation of nuclear factor-KB (NF-KB) via IKB degradation through IKB kinase (IKKA and IKKB) activation, and this resulted in p50 and p65 translocation to the nucleus. Moreover, cells treated with sodium salicylic acid, an IKK inhibitor, or transiently transfected with mutant IKKA and B did not show epothilone-induced cell growth inhibition or p50 translocation, although p65 was still translocated to the nucleus. Treatment with epothilone B and D also enhanced B-tubulin polymerization and the formation of p50/B-tubulin complex. However, B-tubulin polymerization was not inhibited in the cells treated by sodium salicylic acid or transiently transfected with mutant IKKA and B. Moreover, epothilone B and D increased the expressions of NF-KB -dependent apoptotic cell death regulatory genes, i.e., Bax, p53, and the active form of caspase-3, but reduced Bcl-2 expression, and these actions were partially reversed by salicylic acid. In addition, caspase-3 inhibitor reduced epothilone B -induced cell death and NF-KB activation. These findings suggest that the activation of NF-KB/IKK signals plays an important role in the epothilone-induced apoptotic cell death of SW620 colon cancer cells in a tubulin polymerization -independent manner. [Mol Cancer Ther 2007;6(10):2786 -97]

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Section: Introductionmentioning

confidence: 99%

Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway

Lee

Son²,

Son³

et al. 2007

Molecular Cancer Therapeutics

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“…Epothilones suppress microtubule dynamics and are able to trigger a mitotic arrest (8,9). The roles of Aurora kinases in either mitotic arrest or cell death induced by epothilones have not been tested.…”

Section: Taxol and Epothilone B-induced Mitotic Death Requires A Checmentioning

confidence: 99%

“…Epothilones, a relatively new class of drugs, are currently under development for the treatment of cancer. The epothilones may be more effective than taxanes because they are more water-soluble and not subject to P-glycoprotein-mediated resistance (8). Epothilones share a binding site on β-tubulin with Taxol and may induce cell death by similar mechanisms (9).…”

Section: Introductionmentioning

confidence: 99%

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit

Bekier

Fischbach

Lee

et al. 2009

Molecular Cancer Therapeutics

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Cell death induced by agents that disrupt microtubules can kill cells by inducing a prolonged mitotic block. This mitotic block is dependent on the spindle assembly checkpoint, a surveillance system that ensures the bipolar attachment of chromosomes to the mitotic spindle before the onset of anaphase. Under some conditions, the spindle assembly checkpoint can become weakened, allowing cells to exit mitosis despite the presence of chromosomes that are not properly attached to the mitotic spindle. Here, we use an Aurora kinase inhibitor to drive mitotic exit and test the effect of mitotic arrest length on death in the subsequent interphase. Cells that are blocked in mitosis for >15 h die shortly after exiting from mitosis, whereas cells that exit after being blocked for <15 h show variable fates, with some living for days after exiting mitosis. Cells blocked in mitosis by either Taxol or epothilone B are acutely sensitive to the death ligand tumor necrosis factor-related apoptosisinducing ligand, suggesting that prolonged mitosis allows the gradual accumulation of internal death signals, rendering cells hypersensitive to additional prodeath cues. Death under these conditions is initiated while cyclin B1 is still present, indicating that cells are in mitosis. Our experiments suggest that there is a point of no return during prolonged mitotic block after which mitotic exit can no longer block death.

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“…However, taxanes are often of limited efficacy because of the development of cellular resistance such as that mediated by P-glycoprotein-dependent drug efflux (Goodin et al, 2004). The action of TZT-1027 has been suggested to be less affected by multidrug resistance factors, including overexpression of P-glycoprotein, than that of other tubulin inhibitors (Watanabe et al, 2006a), suggesting that TZT-1027 may be effective in the treatment of taxane-refractory tumours.…”

Section: Discussionmentioning

confidence: 99%

The novel microtubule-interfering agent TZT-1027 enhances the anticancer effect of radiation in vitro and in vivo

et al. 2007

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TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect of TZT-1027 on cell cycle progression as well as the anticancer activity of this drug both in vitro and in vivo. With the use of tsFT210 cells, which express a temperature-sensitive mutant of Cdc2, we found that TZT-1027 arrests cell cycle progression in mitosis, the phase of the cell cycle most sensitive to radiation. A clonogenic assay indeed revealed that TZT-1027 increased the sensitivity of H460 cells to g-radiation, with a dose enhancement factor of 1.2. Furthermore, TZT-1027 increased the radiosensitivity of H460 and A549 cells in nude mice, as revealed by a marked delay in tumour growth and an enhancement factor of 3.0 and 2.2, respectively. TZT-1027 also potentiated the induction of apoptosis in H460 cells by radiation both in vitro and in vivo. Histological evaluation of H460 tumours revealed that TZT-1027 induced morphological damage to the vascular endothelium followed by extensive central tumour necrosis. Our results thus suggest that TZT-1027 enhances the antitumour effect of ionising radiation, and that this action is attributable in part to potentiation of apoptosis induction and to an antivascular effect. Combined treatment with TZT-1027 and radiation therefore warrants investigation in clinical trials as a potential anticancer strategy.

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Epothilones: Mechanism of Action and Biologic Activity

Cited by 310 publications

References 34 publications

Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway

Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit

The novel microtubule-interfering agent TZT-1027 enhances the anticancer effect of radiation in vitro and in vivo

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