Increased expression of cyclin E is associated with an increased resistance to doxorubicin in rat fibroblasts

Sgambato, Alessandro; Camerini, Andrea; Pani, Giovambattista; Cangiano, Rodolfo; Faraglia, Beatrice; Bianchino, Gabriella; Bari, Berardino De; Galeotti, T.; Cittadini, Achille

doi:10.1038/sj.bjc.6600970

Cited by 21 publications

(19 citation statements)

References 34 publications

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“…The development of agents capable of targeting cyclin E is highly desirable for the treatment of breast cancer [51] as well as for other types of tumors with dysregulated cyclin E [52, 53, 54]. Deregulation of cyclin E and its LMW isoforms [30, 31] induces chromosome instability [34, 35, 36] and promotes breast cancer tumorigenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

A unique RNA-directed nucleoside analog is cytotoxic to breast cancer cells and depletes cyclin E levels

Stellrecht

Ayres

Arya

et al. 2009

Breast Cancer Res Treat

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In contrast to deoxyribose or arabinose containing nucleoside analogs that are currently established for cancer therapeutics, 8-chloro-adenosine (8-Cl-Ado) possesses a ribose sugar. This unique nucleoside analog is RNA-directed and is in a phase I clinical trial for hematological malignancies. RNA-directed therapies are effective for the treatment of many malignancies as their activities are primarily aimed at short-lived transcripts, which are typically encoded by genes that promote the growth and survival of tumor cells such as cyclin E in breast cancer. Based on this, we hypothesized that 8-Cl-Ado, a transcription inhibitor, will be effective for the treatment of breast cancer cells. The metabolism of 8-Cl-Ado and the effect on ATP in the breast cancer cell lines MCF-7 and BT-474 were measured using HPLC analysis. In these cells, 8-Cl-Ado was effectively taken up, converted to its cytotoxic metabolite, 8-Cl-ATP, and depleted the endogenous ATP levels. This in turn led to an inhibition of RNA synthesis. The RNA synthesis inhibition was associated with a depletion of cyclin E expression, which is indicative of a diminished tumorigenic phenotype. The final outcome of 8-Cl-Ado treatment of the breast cancer cells was growth inhibition due to an induction of apoptosis and a loss of clonogenic survival. These results indicate that 8-Cl-Ado, which is currently in clinic for hematological malignancies, may be an effective agent for the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 99%

A unique RNA-directed nucleoside analog is cytotoxic to breast cancer cells and depletes cyclin E levels

Stellrecht

Ayres

Arya

et al. 2009

Breast Cancer Res Treat

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“…All assays were performed in triplicate and all experiments were repeated at least twice and gave similar results. Cytotoxicity assay was performed as previously reported (Sgambato et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

Caspase‐3 inhibits the growth of breast cancer cells independent of protease activity

Faraglia

Bonsignore²,

Scaldaferri

et al. 2004

Journal Cellular Physiology

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In this study, the MCF-7 breast cancer cells that lack caspase-3 were transfected with a wild type (WT) or mutant caspase-3 cDNA. Expression of the WT, but not of the mutant, caspase-3 was associated with increased caspase activity and susceptibility to staurosporine (STS)-induced apoptosis. Both derivatives displayed inhibition of cell growth compared with vector control cells. Growth inhibition was associated with increased expression of the cyclin dependent kinase (CDK) inhibitor p27Kip1 in the WT, but not in the mutant caspase-3 expressing cells. Cyclin D1 expression level was not affected by caspase-3 expression. Phosphorylation of the Akt protein was decreased in both WT and mutant caspase transfected cells, although Akt expression level remained unchanged. These results suggest that caspase-3 might have biological functions independent of its protease activity and that its loss might contribute to tumor development by increasing the growth potential of cancer cells.

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“…Moreover, oncogenic K-Ras, but not H-Ras, has been shown to increase MnSOD activity in a post-translational fashion [87]. Finally, cyclin E overexpression in rodent fibroblast leads to increased MnSOD expression and resistance to doxorubicin [88].…”

Section: A Rationale For Mnsod Inhibition In Cancer Therapymentioning

confidence: 98%

Mitochondrial Superoxide Dismutase: A Promising Target for New Anticancer Therapies

Pani¹,

Colavitti²,

Bedogni³

et al. 2004

CMC

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Compelling experimental and epidemiological evidence involves oxygen radicals in carcinogenesis, acting reactive oxygen species both as endogenous genotoxins during cell initiation and as messenger molecules in mitogenesis and in tumor promotion. Moreover, oxidants stimulate neoangiogenesis, which is a prerequisite for tumor growth. However, while several natural as well as synthetic antioxidant compounds appear to be chemopreventive in mutagenicity assays, antioxidant-based treatments for the prevention or cure of cancer have led to non-conclusive if not disappointing results. This is likely due to the fact that oxygen radicals have also a major role in the natural defences against the propagation of cancer cells, i.e. tumor cell apoptosis and immune surveillance, and mediate the beneficial cytotoxic effect of both the chemo-and radio-therapy. In recent years, the mitochondrial antioxidant enzyme, Manganous Superoxide Dismutase (MnSOD), has received a growing attention as a negative modulator of cellular apoptosis and as a survival factor for cancer cells. In fact, while overexpression of this enzyme in cancer cells decreases proliferation and tumor incidence in transgenic models, it is clear that even small amounts of this enzyme are crucial for cell resistance to inflammatory stimuli and anticancer drugs, and prevent oncogene-induced apoptosis triggered by the tumor suppressor protein p53. A previously unexpected oncogenic potential of MnSOD is also suggested by the elevated levels of this enzyme in several classes of human neoplasms, in a fashion which often correlates with the degree of their malignancy. This review focuses on the debated issue of the pro- and/or anti-tumoral effect of MnSOD, with special emphasis on recent observations suggesting that pharmacological inhibition of MnSOD may represent an effective strategy to selectively kill cancer cells and to circumvent their resistance to the commonly used anticancer treatments.

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Increased expression of cyclin E is associated with an increased resistance to doxorubicin in rat fibroblasts

Cited by 21 publications

References 34 publications

A unique RNA-directed nucleoside analog is cytotoxic to breast cancer cells and depletes cyclin E levels

A unique RNA-directed nucleoside analog is cytotoxic to breast cancer cells and depletes cyclin E levels

Caspase‐3 inhibits the growth of breast cancer cells independent of protease activity

Mitochondrial Superoxide Dismutase: A Promising Target for New Anticancer Therapies

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