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

Cun, Biyun; Song, Xin; Jia, Renbing; Zhao, Xiaoping; Wang, Haibo; Ge, Shengfang; Fan, Xianqun

doi:10.4161/cbt.13.2.18436

Cited by 18 publications

(21 citation statements)

References 29 publications

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“…Previous studies have indicated that high doses of DTIC (2 mM) result in the death of cancer cells through apoptosis (33). In addition, in uveal melanoma cell lines, DTIC treatment (5 µg/ml) primarily led to cell cycle arrest in the G1 phase (34). Another previous study demonstrated that DTIC (1 mM) induces S-phase cell cycle arrest in A375 cells and results in a slight increase in the sub-G1 peak (35).…”

Section: Discussionmentioning

confidence: 99%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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Abstract. Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anticancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma. IntroductionMelanoma is a particularly aggressive skin cancer and its incidence is increasing faster than any other cancer worldwide (1). At present, the 10-year survival rate of patients diagnosed with advanced (stage IV) metastatic melanoma is <10% (2), which highlights the importance of early detection and treatment. The Food and Drug Administration approved the chemotherapeutic agent dacarbazine (DTIC) for the treatment of metastatic melanoma in 1975, and it remains the only licensed chemotherapeutic agent in use today (1). DTIC is a methylating agent which causes DNA damage, cell cycle arrest and apoptosis. Despite this, only 2% of all patients with metastatic melanoma receiving this treatment demonstrate a significant response and only 11.2% demonstrate a partial response (3). Resistance to DTIC has been associated with the upregulation of pro-survival signals and anti-apoptotic molecules in cancer cells. Despite its moderate effects, DTIC continues to be the standard treatment for metastatic melanoma as no other chemotherapeutic treatment has been demonstrated to have a significantly increased chance of survival when compared with DTIC (4,5). Provided the limited efficacy of the current metastatic melanoma chemotherapies in addition to the increasing incidence of melanoma cases, there appears to be a need for the development of more effective treatment strategies.Statins are a group of drugs commonly used for the reduction of cholesterol levels (6). They work by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a critical enzyme in the mevalonate pathway, which is responsible for cholesterol synthesis (6,7). In addition, statins have been de...

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Section: Discussionmentioning

confidence: 99%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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“…The previously characterized human uveal melanoma cell lines OM431, VUP, SP6.5 and OCM1 were kindly provided by Professor John F. Marshall (Tumor Biology Laboratory, John Vane Science Centre, London, UK) [20,32]. ARPE-19 cells were obtained from the American Type Culture Collection (Manassas, VA, USA).…”

Section: Methodsmentioning

confidence: 99%

The Pharmacological NF-κB Inhibitor BAY11-7082 Induces Cell Apoptosis and Inhibits the Migration of Human Uveal Melanoma Cells

Luo

Cun

et al. 2012

IJMS

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Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma.

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“…Novel progeny viruses released from host cells infect neighboring cells continually and ultimately eliminate tumor cells. The combination of viral and gene therapy developed into the novel strategy of gene-viro therapy, in which therapeutic genes amplified abundantly with adenovirus replication and functioned as antitumor agents (31,32). Recently, it has been demonstrated that the combination of replication-selective oncolytic adenoviruses with chemotherapeutic agents is a promising cancer therapy (33).…”

Section: Discussionmentioning

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

Cited by 18 publications

References 29 publications

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

The Pharmacological NF-κB Inhibitor BAY11-7082 Induces Cell Apoptosis and Inhibits the Migration of Human Uveal Melanoma Cells

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

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