Low-dose paclitaxel synergizes with oncolytic adenoviruses via mitotic slippage and apoptosis in ovarian cancer

Ingemarsdotter, Carin K.; Baird, Sarah K.; Connell, Claire M.; Öberg, Daniel; Halldén, Gunnel; McNeish, Iain A.

doi:10.1038/onc.2010.335

Cited by 48 publications

(41 citation statements)

References 42 publications

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“…Spread relies both upon release of virus from initially infected cells as well as upon subsequent infection of neighboring cells. Although adenovirus release is largely lytic, we have recently shown that a nonlytic mechanism may exist, dependent upon stabilized microtubules (42). The in vitro experiments described here lasted for 5 days at most, which allowed approximately 2-3 rounds of replication (43).…”

Section: Figurementioning

confidence: 99%

Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Connell¹,

Shibata²,

Tookman³

et al. 2011

J. Clin. Invest.

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Oncolytic adenoviruses replicate selectively within and lyse malignant cells. As such, they are being developed as anticancer therapeutics. However, the sensitivity of ovarian cancers to adenovirus cytotoxicity varies greatly, even in cells of similar infectivity. Using both the adenovirus E1A-CR2 deletion mutant dl922-947 and WT adenovirus serotype 5 in a panel of human ovarian cancer cell lines that cover a 3-log range of sensitivity, we observed profound overreplication of genomic DNA only in highly sensitive cell lines. This was associated with the presence of extensive genomic DNA damage. Inhibition of ataxia telangiectasia and Rad3-related checkpoint kinase 1 (ATR-Chk1), but not ataxia telangiectasia mutated (ATM), promoted genomic DNA damage and overreplication in resistant and partially sensitive cells. This was accompanied by increased adenovirus cytotoxicity both in vitro and in vivo in tumor-bearing mice. We also demonstrated that Cdc25A was upregulated in highly sensitive ovarian cancer cell lines after adenovirus infection and was stabilized after loss of Chk1 activity. Knockdown of Cdc25A inhibited virus-induced DNA damage in highly sensitive cells and blocked the effects of Chk1 inhibition in resistant cells. Finally, inhibition of Chk1 decreased homologous recombination repair of virus-induced genomic DNA double-strand breaks. Thus, virus-induced host cell DNA damage signaling and repair are key determinants of oncolytic adenoviral activity, and promoting unscheduled DNA synthesis and/or impeding homologous recombination repair could potentiate the effects of oncolytic adenoviruses in the treatment of ovarian cancer.

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Section: Figurementioning

confidence: 99%

Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Connell¹,

Shibata²,

Tookman³

et al. 2011

J. Clin. Invest.

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“…1 Here we choose the combination of chemotherapy rather than radiotherapy and adenovirus is intended to explore a new way of topical chemotherapy plus topical injection of oncolytic virus to treat uveal melanoma. Next, some studies of the described combination treatment for other tumor type observed an augmentation of apoptosis [12][13][14][15] while our investigation demonstrated that whether monotherapy of DTIC or H101, or co-treatment appears to be related to cell cycle blocking instead of apoptosis. Meanwhile we observed DTIC did not enhance the killing ability of H101 through upregulation of cell entry or virus replication.…”

Section: Discussionmentioning

confidence: 97%

“…A synergistic tumor cell killing ability has been previously observed in the combination therapy of various adenoviruses with chemicals due to the augmentation of apoptosis. [12][13][14][15] Chemotherapy, which is mediated by a different mechanism, often induces distinct toxicity and causes multiple side effects, whereas oncolytic adenovirus exhibits greater tumor selectivity. Thus, in combination they potentially act synergistically without overlapping toxicity.…”

Section: Introductionmentioning

confidence: 99%

Combination of oncolytic adenovirus and dacarbazine enhances antitumor ability against uveal melanoma cells via cell cycle block

Cun¹,

Song²,

Jia³

et al. 2012

Cancer Biology & Therapy

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These authors contributed equally to this work.Keywords: uveal melanoma, oncolytic adenovirus, dacarbazine, combination therapy, cell cycle Uveal melanoma is the most common primary intraocular malignancy in adults; however, current therapeutic modalities, including chemotherapy, have not been successful. Oncolytic viruses serve as an emerging gene therapy tool for cancer treatment because they specifically kill tumor cells while sparing normal cells. The oncolytic virus H101 has been approved by the Chinese State Food and Drug Administration for the treatment of certain malignancies. Unfortunately, the monotherapy of adenovirus has demonstrated limited efficacy in a clinical setting. Thus, novel treatment strategies in which an oncolytic virus is combined with existing chemicals are advancing toward potential clinical use. In this study, we chose the combination of oncolytic virus H101 and the alkylating agent dacarbazine (DTIC) to treat uveal melanoma cells in vitro. Our results demonstrated that the combination exerted a synergistic antitumor effect without enhanced toxicity to normal cells via a type of cell cycle block other than the induction of apoptosis. Further investigation is warranted to elucidate the specific underlying mechanisms of this co-treatment therapy. Our study suggests the virochemo combination therapy is feasible and is a potentially promising approach for the treatment of uveal melanoma.

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“…A modest response of dl922-947 was also reported in combination with gemcitabine in pancreatic cancer cells compared with trials using the virus alone (25,26). The microtubule-stabilizing drug paclitaxel (PTX) exhibits activity in relapsed cancer and regimes containing a weekly low-dose PTX are highly effective (27).…”

Section: Introductionmentioning

confidence: 99%

An oncolytic adenovirus expressing interleukin-24 enhances antitumor activities in combination with paclitaxel in breast cancer cells

Lin

Qian

Bai

et al. 2013

Molecular Medicine Reports

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Abstract. Oncolytic adenoviruses are a novel class of anticancer treatment, based upon their ability to replicate selectively within malignant cells resulting in cell lysis. The replication-selective adenovirus, ZD55-IL-24, was constructed by harboring an E1B-55 kDa deletion and arming with interleukin-24 (IL-24). The microtubule-stabilizing drug paclitaxel (PTX) exhibits activity in relapsed cancer. In the present study, the synergistic antitumor effects of the combination of PTX and ZD55-IL-24 on breast cancer cells was investigated. The results demonstrated that there were different roles for PTX in the expression of transgenic mRNA and protein. ZD55-IL-24 combined with PTX induced marked growth inhibition of MDA-MB-231 and Bcap-37 cells. PTX increased viral uptake and appeared not to alter the replication of ZD55-IL-24 in breast cancer cells. Annexin V-fluorescein isothiocyanate/propidium iodide staining and the Hoechst 33258 assay indicated that ZD55-IL-24 induced an increase in the number of apoptotic cells when administered in combination with PTX. It was demonstrated that ZD55-IL-24 conjugated with PTX was highly concomitant, and increased proapoptotic proteins levels, activated caspase-3, -7 and -9 and downregulated anti-apoptotic proteins. These results suggested that ZD55-IL-24 in combination with PTX exhibited a markedly increased cytotoxic and apoptosis-inducing effect in breast cancer cells. Thus, this chemo-gene-viro therapeutic strategy was demonstrated to be superior to conventional chemotherapy or gene-viro therapy alone.

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Low-dose paclitaxel synergizes with oncolytic adenoviruses via mitotic slippage and apoptosis in ovarian cancer

Cited by 48 publications

References 42 publications

Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Combination of oncolytic adenovirus and dacarbazine enhances antitumor ability against uveal melanoma cells via cell cycle block

An oncolytic adenovirus expressing interleukin-24 enhances antitumor activities in combination with paclitaxel in breast cancer cells

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