Taxol-induced cell cycle arrest and apoptosis: dose–response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition

Das, Gautam; Holiday, David; Gallardo, Rafael L.; Haas, Charles

doi:10.1016/s0304-3835(01)00404-9

Cited by 82 publications

(65 citation statements)

References 12 publications

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“…The findings derived from our study comparing human lung cancer cells and human lung fibroblasts also imply that cell death induced by taxanes occurs through a p53-independent pathway; i.e., no alteration of p53 expression was observed in human lung fibroblasts treated with different docetaxel concentrations, although the IC 50 values and morphological changes were similar to those seen in H460 and A549 lung cancer cells (data not shown). Although p53 seems to be dispensable for taxane-induced apoptosis (42)(43)(44), increased expression of p53 occurs coincidentally with the enhancement of apoptosis in the p53 wild-type cell lines H460 and A549 treated with ß-elemene in combination with paclitaxel or docetaxel in our study. Given that taxanes exerted much stronger cytotoxicity in p53 wild-type H460 and A549 cells than in p53 mutation-type H23 cells or p53 null-type H358 cells, our findings suggest that p53 acts at least as a 'promoter' gene in taxane-induced apoptotic cell death.…”

Section: Discussionmentioning

confidence: 47%

In vitro combination characterization of the new anticancer plant drug β-elemene with taxanes against human lung carcinoma

Zhao

Zou

et al. 2007

Int J Oncol

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Abstract. ß-elemene has recently raised interest in P.R. China as a novel antitumor plant drug isolated from the Chinese medicinal herb Zedoary. To explore potentially useful combinations of ß-elemene with taxanes in the clinic, we characterized the effects of ß-elemene combined with taxanes in human lung cancer cells using a median effect analysis, micronucleus assay, apoptotic detection, and determination of gene expression in the signaling pathways of apoptosis. The synergistic analysis indicated that the interactions of ß-elemene with paclitaxel or docetaxel ranged from slight synergism to synergism. Combinations of ß-elemene with docetaxel induced much stronger synergistic interactions in p53 mutant H23 cells and p53 null H358 cells than in p53 wild-type H460 and A549 cells. Similar synergistic interactions were observed by micronucleus assay, apoptotic detection, and determination of apoptotic gene expression. Our findings indicate that the synergistic effects achieved with combinations of ß-elemene and taxanes are related to the augmented cytotoxic efficacy of taxanes owing to the action of ß-elemene. In H460 and A549 cells, dose-dependent upregulation of p53 protein expression was observed in cultures treated with docetaxel alone and with docetaxel plus ß-elemene, whereas no significant change in p53 expression was observed in any of the treatment groups in H23 cells. Fas revealed no alteration of expression with any of the treatments in this study. However, the combination treatments induced increased cytochrome c release from mitochondria, significant caspase-8 and -3 cleavage, and downregulation of Bcl-2 and Bcl-X L expression. These results suggest that, although p53 plays an important role in taxaneinduced cell death, apoptosis induced by ß-elemene or in combination with docetaxel thereof seems to be initiated through a p53-and Fas-independent pathway via mitochondria in our lung cancer cells. The suppression of specific 'survival' gene expression appears to be the key action leading to the synergistic effect of combination treatments with ß-elemene and taxanes. Finally, the ß-elemene-induced alteration of cell membrane permeability, which has potential to result in enhanced cellular uptake of taxanes, may also contribute to the synergistic interactions of the combination treatments.

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Section: Discussionmentioning

confidence: 47%

In vitro combination characterization of the new anticancer plant drug β-elemene with taxanes against human lung carcinoma

Zhao

Zou

et al. 2007

Int J Oncol

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“…Previous studies with NSCLC A549 cells also found that low concentrations of paclitaxel are sufficient to induce cell death without an apparent G 2 -M block (36,37). The exact mechanism is not fully understood, although aberrant mitosis and p53 induction have been suggested as possible mechanisms (36,38).…”

Section: Discussionmentioning

confidence: 96%

Class III β-Tubulin Mediates Sensitivity to Chemotherapeutic Drugs in Non–Small Cell Lung Cancer

Gan

Pasquier²,

Kavallaris³

2007

Cancer Research

196

180

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First line therapy for non-small cell lung carcinoma (NSCLC) commonly includes combination therapy with a tubulinbinding agent (TBA) and a DNA-damaging agent. TBAs suppress microtubule dynamics by binding to the B-tubulin subunit of A/B-tubulin, inducing mitotic arrest and apoptosis. Up-regulation of class III B-tubulin (BIII-tubulin) has been implicated in clinical resistance in NSCLC, ovarian and breast tumors treated in combination with a TBA and DNAdamaging agent. To investigate the functional significance of BIII-tubulin in resistance to both these classes of agents, small interfering RNA (siRNA) was used to silence the expression of this isotype in two NSCLC cell lines, NCI-H460 and Calu-6. Reverse transcription-PCR and immunoblotting showed that BIII-siRNA potently inhibited the expression of BIII-tubulin, without affecting the expression of other major B-tubulin isotypes. Clonogenic assays showed that BIII-siRNA cells were significantly more sensitive to TBAs, paclitaxel, vincristine, and vinorelbine, and for the first time, DNA-damaging agents, cisplatin, doxorubicin, and etoposide compared with controls. Cell cycle analysis of H460 BIII-siRNA cells showed reduced accumulation at the G 2 -M boundary and an increase in the sub-G 1 population in response to TBA treatment compared with control cells. Importantly, BIII-siRNA cells displayed a significant dose-dependent increase in Annexin V staining when treated with either paclitaxel or cisplatin, compared with controls. These findings have revealed a novel role for BIII-tubulin in mediating response to both TBA and DNAdamaging agent therapy and may have important implications for improving the targeting and treatment of drug-refractory NSCLC.

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“…Two agents that showed significant combined effects with ZOL such as PAC and GEM revealed different effects of the alteration of cell cycle in osteosarcoma cells. PAC accumulated cells in G 2 /M phase, resulting the induction of apoptosis (Das et al, 2001), while GEM seemed to induce apoptosis in S phase (Shi et al, 2001) (Table 3). These findings suggest that it is difficult to predict which agent becomes a good partner for ZOL based on its activity on the alteration of cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

et al. 2007

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Bisphosphonates (BPs) are widely used to treat bone diseases and also appear to possess direct antitumour activity. We have previously reported that third-generation BPs such as zoledronic acid (ZOL) and minodronic acid (YM529) synergistically augment the effects of anticancer agents in various cancer cells. Recently, we have also reported the antitumour effects of YM529 on murine osteosarcoma cells. As YM529 has not been clinically available, we herein focused on the anti-osteosarcoma effects of ZOL which is clinically available. In addition to ZOL alone, we evaluated the concurrent or sequential combined effects of ZOL with other anticancer agents against murine osteosarcoma cell lines. ZOL showed almost same anti-osteosarcoma activity compared with YM529 and more sensitive growth inhibitory effects against osteosarcoma cells than normal cells. Moreover, ZOL acted synergistically in vitro when administered concurrently with paclitaxel (PAC) or gemcitabine (GEM), not only in wild-type osteosarcoma cells but also in P-glycoprotein (P-gp)-overexpressing osteosarcoma cells, which were much less sensitive against each anticancer agent. Furthermore, 24 h of ZOL pretreatment significantly augmented the sensitivity of doxorubicin (DOX), PAC or GEM against osteosarcoma cells. These findings suggest that combined administration of ZOL with other anticancer agents may improve the osteosarcoma treatment.

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Taxol-induced cell cycle arrest and apoptosis: dose–response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition

Cited by 82 publications

References 12 publications

In vitro combination characterization of the new anticancer plant drug β-elemene with taxanes against human lung carcinoma

In vitro combination characterization of the new anticancer plant drug β-elemene with taxanes against human lung carcinoma

Class III β-Tubulin Mediates Sensitivity to Chemotherapeutic Drugs in Non–Small Cell Lung Cancer

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

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