The tubulin-depolymerising agent combretastatin-4 induces ectopic aster assembly and mitotic catastrophe in lung cancer cells H460

Cenciarelli, Chiara; Tanzarella, Caterina; Vitale, Ilio; Pisano, Claudio; Crateri, Pasqualina; Meschini, Stefania; Arancia, Giuseppe; Antoccia, Antonio

doi:10.1007/s10495-008-0200-2

Cited by 39 publications

(32 citation statements)

References 47 publications

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“…These drug exposures are relevant for in vivo studies, where mouse plasma levels of the active CA4P metabolite CA4 were reported in the region of 0.5-2.8 lM, within 90 min of administering 100 mg/kg CA4P. 29,43 Our data confirmed several previous studies [24][25][26][27][28] showing that the mode of direct tumor cell death was anti-proliferative, leading to apoptosis, and that resistance to CA4P was indeed maintained in vivo, since markers of apoptosis, namely DNA fragmentation and cleaved caspase-3 expression were significantly greater in SW1222…”

Section: Discussionsupporting

confidence: 90%

“…Previous in vitro studies have shown CA4P-mediated cytotoxicity to be a result of mitotic arrest and apoptosis. [26][27][28] Tumor cell apoptosis was examined in both lines following treatment with CA4P for 24 hr. Consistent with the tumor cell viability data, the SW1222…”

Section: The Sw1222mentioning

confidence: 99%

“…23 In vitro, CA4P inhibits tumor cell proliferation and causes mitotic arrest by interfering with mitotic spindles and chromosome attachment. [24][25][26][27][28] These effects are dependent on both level and duration of drug exposure. Mitotic-arrested cells subsequently undergo mitotic catastrophe and apoptosis through caspase-dependent and -independent mechanisms.…”

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confidence: 99%

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Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Lunt

Akerman

Hill

et al. 2011

Intl Journal of Cancer

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Vascular‐targeted therapeutics are increasingly used in the clinic. However, less is known about the direct response of tumor cells to these agents. We have developed a combretastatin‐A‐4‐phosphate (CA4P) resistant variant of SW1222 human colorectal carcinoma cells to examine the relative importance of vascular versus tumor cell targeting in the ultimate treatment response. SW1222Res cells were generated through exposure of wild‐type cells (SW1222WT) to increasing CA4P concentrations in vitro. Increased resistance was confirmed through analyses of cell viability, apoptosis and multidrug‐resistance (MDR) protein expression. In vivo, comparative studies examined tumor cell necrosis, apoptosis, vessel morphology and functional vascular end‐points following treatment with CA4P (single 100 mg/kg dose). Tumor response to repeated CA4P dosing (50 mg/kg/day, 5 days/week for 2 weeks) was examined through growth measurement, and ultimate tumor cell survival was studied by ex vivo clonogenic assay. In vitro, SW1222Res cells showed reduced CA4P sensitivity, enhanced MDR protein expression and a reduced apoptotic index. In vivo, CA4P induced significantly lower apoptotic cell death in SW1222Res versus SW1222WT tumors indicating maintenance of resistance characteristics. However, CA4P‐induced tumor necrosis was equivalent in both lines. Similarly, rapid CA4P‐mediated vessel disruption and blood flow shut‐down were observed in both lines. Cell surviving fraction was comparable in the two tumor types following single dose CA4P and SW1222Res tumors were at least as sensitive as SW1222WT tumors to repeated dosing. Despite tumor cell resistance to CA4P, SW1222Res response in vivo was not impaired, strongly supporting the view that vascular damage dominates the therapeutic response to this agent.

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Section: Discussionsupporting

confidence: 90%

Section: The Sw1222mentioning

confidence: 99%

mentioning

confidence: 99%

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Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Lunt

Akerman

Hill

et al. 2011

Intl Journal of Cancer

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“…Similarly, 4 and a combretastatin derivative induced mitotic catastrophe dependent on spindle checkpoint and caspase-3 activation in non-small cell lung cancer cells [33,34]. Mitotic catastrophe has also been demonstrated for 4 and related derivatives in both human endothelial cells (HUVEC) and human lung carcinoma cells (H460) [35].…”

Section: Antiproliferative Activity In Breast Cancer Cellsmentioning

confidence: 87%

Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

O’Boyle

Carr

Greene

et al. 2011

European Journal of Medicinal Chemistry

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“…Another possible cause of spindle multipolarity is the presence of multiple centrosomes that can be formed by centrosome fragmentation or duplication (31,32). It has been reported that loss of centrosome integrity in association with multipolar spindle formation can be induced by different chemical agents, including estrogens (33), combretastatin (34), rotenone (35), and arsenite (36). 4-Oxo-4-HPR-induced multipolar spindles exhibited only two centrosomes, which were visualized by γ-tubulin staining.…”

Section: Discussionmentioning

confidence: 99%

Antimitotic effect of the retinoid 4-oxo-fenretinide through inhibition of tubulin polymerization: a novel mechanism of retinoid growth–inhibitory activity

Appierto

Tiberio

Cavadini

et al. 2009

Molecular Cancer Therapeutics

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The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR-treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unlike 4-HPR, causes marked cell accumulation in G 2 -M phase. Here, we investigated the molecular events involving 4-oxo-4-HPR-induced cell cycle perturbation in ovarian (A2780 and IGROV-1) and breast (T47D, estrogen receptor+ and BT-20, estrogen receptor-) cancer cells. 4-Oxo-4-HPR induced a delay of mitosis (with mitotic index increasing 5-to 6-fold in all cell lines) without progression beyond the anaphase, as shown by cyclin B1 expression. 4-Oxo-4-HPR induced multipolar spindle formation and phosphorylation of BUBR1, resulting in activation of the spindle checkpoint. Multipolar spindles were not due to impairment of pole-focusing process, loss of centrosome integrity, or modulation of the expression levels of molecules associated with spindle aberrations (Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp). We show here that 4-oxo-4-HPR targets microtubules because, in treated cells, it interfered with the reassembly of cold-depolymerized spindle microtubules and decreased the polymerized tubulin fraction. In cell-free assays, 4-oxo-4-HPR inhibited tubulin polymerization (50% inhibition of microtubule assembly at 5.9 μmol/L), suggesting a direct molecular interaction with tubulin. In conclusion, by showing that 4-oxo-4-HPR causes mitotic arrest through antimicrotubule activities, we delineate a new molecular mechanism for a retinoid.

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The tubulin-depolymerising agent combretastatin-4 induces ectopic aster assembly and mitotic catastrophe in lung cancer cells H460

Cited by 39 publications

References 47 publications

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

Antimitotic effect of the retinoid 4-oxo-fenretinide through inhibition of tubulin polymerization: a novel mechanism of retinoid growth–inhibitory activity

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