Apoptins: selective anticancer agents

Peñaloza, Oscar M. Rollano; Lewandowska, Magdalena; Stetefeld, Jörg; Ossysek, Karolina; Madej, Mariusz; Bereta, Joanna; Sobczak, Mateusz; Shojaei, Shahla; Ghavami, Saeid; Łos, Marek

doi:10.1016/j.molmed.2014.07.003

Cited by 34 publications

(24 citation statements)

References 105 publications

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“…Due to the very diverse roles of the proteins, and the differences between cell types and tissues, the therapeutic effects based on inhibition of the mevalonate pathway are varying, and the approach is not applicable as a general anticancer strategy, as only some tumor types are susceptible to this treatment (Fritz, 2009;Swanson and Hohl, 2006). A better therapeutic strategy could be achieved by targeting the mevalonate pathway in combination with other standard, or experimental treatments, like apoptins (Chaabane et al, 2014;Rollano Penaloza et al, 2014), or drugs preferentially targeting CSC, like salinomycin (Jangamreddy et al, 2013). Beside Ras and Rho, the function of several other proteins could be dramatically affected by subcellular localization.…”

Section: Discussionmentioning

confidence: 99%

Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

Likus

Siemianowicz

Bieńk

et al. 2016

Drug Resistance Updates

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Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of Abbreviations: ACAT, acetoacetyl-CoA transferase; acetyl-CoA, acetyl-coenzyme A; Arp2/3, actin-related protein 2/3 (actin polymerizing complex) BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/). 14 W. Likus et al. / Drug Resistance Updates 25 (2016) 13-25 the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.

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Section: Discussionmentioning

confidence: 99%

Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

Likus

Siemianowicz

Bieńk

et al. 2016

Drug Resistance Updates

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“…It has been shown that apoptin can be introduce to various tumor cells using different delivery strategies in the form of encoding DNA or protein (Los et al 2009; Peñaloza et al 2014). Viral-mediated apoptin gene delivery has been widely used to investigate the anticancer activity of apoptin (Pietersen et al 1999; Pan et al 2010; Ma et al 2012; Wu et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The cancer-selective toxicity of apoptin is largely related to differences in the subcellular localization of the protein. Apoptin is predominantly accumulated in the nucleus of transformed cells, whereas in normal cells it is found mainly in the cytoplasm (Heilman et al 2006; Kuusisto et al 2008; Noteborn 2004; Peñaloza et al 2014). Apoptin can be phosphorylated in several phosphorylation sites by certain kinases, which are upregulated in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

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A novel anti-CD22 scFv–apoptin fusion protein induces apoptosis in malignant B-cells

et al. 2017

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CD22 marker is a highly internalizing antigen which is located on the surface of B-cells and is being used as a promising target for treatment of B cell malignancies. Monoclonal antibodies targeting CD22 have been introduced and some are currently under investigation in clinical trials. Building on the success of antibody drug conjugates, we developed a fusion protein consisting of a novel anti-CD22 scFv and apoptin and tested binding and therapeutic effects in lymphoma cells. The recombinant protein was expressed in E. coli and successfully purified and refolded. In vitro binding analysis by immunofluorescence and flow cytometry demonstrated that the recombinant protein specifically binds to CD22 positive Raji cells but not to CD22 negative Jurkat cells. The cytotoxic properties of scFv–apoptin were assessed by an MTT assay and Annexin V/PI flow cytometry analysis and showed that the recombinant protein induced apoptosis preferentially in Raji cells with no detectable effects in Jurkat cells. Our findings indicated that the recombinant anti-CD22 scFv–apoptin fusion protein could successfully cross the cell membrane and induce apoptosis with high specificity, make it as a promising molecule for immunotherapy of B-cell malignancies.

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“…However, we did not observe significant differences between HT-29 and LS-180 cells derived from different grade tumors (Duke's stage 1 and Duke's stage 2, respectively) (data not shown). Moreover, it was reported that not only activation of Akt kinase but also its cellular localization may determine the biological response to specific signal transduced by the mentioned kinase (Maddika et al, 2009;Rollano Peñaloza et al, 2014). The nuclear fraction of Akt is suggested as an apoptosis stimulator, interacting with apoptotin, one of the proteins involved in induction of apoptosis (Maddika et al, 2007).…”

Section: Discussionmentioning

confidence: 99%