More about salinomycin

New mission for salinomycin in cancer by Cord Naujokat, SciTopics, July 15, 2010. Excerpt (in the "continue reading" section):

In addition, a very recent study demonstrates that salinomycin overcomes ATP-binding cassette (ABC) transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like cells (3).

Reference #3: Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells, by Dominik Fuchs and 4 co-authors, including Cord Naujokat, Biochem Biophys Res Commun 2010(Apr 16);394(4): 1098-104 [Epub 2010(Mar 27)][PubMed citation].

Comments: Near the end of this article about salinomycin is the comment that "the investigation of its safety, toxicity, pharmacology and anticancer activity in humans will be a challenge." The author then mentions a preliminary study of "a small cohort of patients with metastatic breast cancer or metastatic head and neck cancers". The results of this preliminary study of the toxicity of salinomycin are summarized. They have not yet been published in the peer-reviewed literature, although a manuscript has been submitted [see reference #4 in the article]. The implication of these preliminary results is that there may be a "therapeutic window" for salinomycin, that is, a drug dosage that yields clinically significant benefits in the absence of excessive toxicity.

For a previous commentary on salinomycin, see: Cancer stem cell breakthrough by Kat Arney, Science Update blog, Cancer Research UK, August 14, 2009. Excerpt:

We need to stress that these were laboratory experiments, and there is no evidence yet that salinomycin can treat cancer in humans. Salinomycin is currently used as an antibiotic for chickens and cows, and it can be toxic or even fatal to humans, causing serious muscle and heart problems.

If there is a "therapeutic window" for salinomycin, it could be a small one, and is likely to vary from one tumor to another.

For a previous post to this blog about salinomycin, see: Identification of selective inhibitors of breast CSCs in mice, August 14, 2009.

Targeting A20 Decreases Glioma SC Survival and Tumor Growth

Targeting A20 Decreases Glioma Stem Cell Survival and Tumor Growth by Anita B Hjelmeland and 10 co-authors, including Jeremy N Rich, PLoS Biol 2010(Feb 23); 8(2): e1000319 [FriendFeed entry][Connotea bookmark].

For a news release about this publication, see: Researchers identify a potential therapeutic target for brain cancer, EurekAlert, February 22, 2010. First paragraph:

Researchers at the Cleveland Clinic report the identification of a protein that is highly expressed in a subgroup of glioblastoma brain tumor cells and show that depletion of this protein increases the survival of mice with these tumors. This work will be published in the online open-access journal PLoS Biology.

Analyzing tumors as ecosystems

Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype by So Yeon Park and 4 co-authors, including Kornelia Polyak, J Clin Invest 2010(Jan 25) [Epub ahead of print][FriendFeed entry][Connotea bookmark][Full text is publicly accessible (via Gratis OA)]. PubMed Abstract:

Intratumor genetic heterogeneity is a key mechanism underlying tumor progression and therapeutic resistance. The prevailing model for explaining intratumor diversity, the clonal evolution model, has recently been challenged by proponents of the cancer stem cell hypothesis. To investigate this issue, we performed combined analyses of markers associated with cellular differentiation states and genotypic alterations in human breast carcinomas and evaluated diversity with ecological and evolutionary methods. Our analyses showed a high degree of genetic heterogeneity both within and between distinct tumor cell populations that were defined based on markers of cellular phenotypes including stem cell-like characteristics. In several tumors, stem cell-like and more-differentiated cancer cell populations were genetically distinct, leading us to question the validity of a simple differentiation hierarchy-based cancer stem cell model. The degree of diversity correlated with clinically relevant breast tumor subtypes and in some tumors was markedly different between the in situ and invasive cell populations. We also found that diversity measures were associated with clinical variables. Our findings highlight the importance of genetic diversity in intratumor heterogeneity and the value of analyzing tumors as distinct populations of cancer cells to more effectively plan treatments.

The final sentence of the Discussion section of the full text:

In summary, in this study we have demonstrated the power of analyzing tumors as ecosystems and suggest that quantitative measures of intratumor diversity might be clinically useful biomarkers predicting prognosis and response to treatment.

Another recent article from the same group: Heterogeneity for Stem Cell–Related Markers According to Tumor Subtype and Histologic Stage in Breast Cancer by So Yeon Park and 5 co-authors, including Kornelia Polyak, Clin Cancer Res 2010; 16(3): 876–87 [Epub 2010(Jan 26)][FriendFeed entry][Connotea bookmark][PubMed Citation].

From the Conclusions section of the abstract:

Our findings suggest that in breast cancer, the frequency of tumor cells positive for stem cell-like and more differentiated cell markers varies according to tumor subtype and histologic stage.

Ovarian CSCs play a role in tumor neovascularization?

Stem-like Ovarian Cancer Cells can Serve as Tumor Vascular Progenitors by Ayesha B Alvero and 8 co-authors, including Gil Mor, Stem Cells 2009(Aug 5) [Epub ahead of print]. PubMed Abstract:

Neovascularization is required for solid tumor maintenance, progression, and metastasis. The most described contribution of cancer cells in tumor neovascularization is the secretion of factors, which attract various cell types to establish a microenvironment that promote blood vessel formation. The cancer stem cell hypothesis suggests that tumors are composed of cells that may share the differentiation capacity of normal stem cells. Similar to normal stem cells, cancer stem cells (CSCs) have the capacity to acquire different phenotypes. Thus, it is possible that CSCs have a bigger role in the process of tumor neovascularization. In this study, we show the capacity of a specific population of ovarian cancer cells with stem-like properties to give rise to xenograft tumors containing blood vessels, which are lined by human CD34+ cells. In addition, when cultured in high-density Matrigel, these cells mimic the behavior of normal endothelial cells and can form vessel-like structures in 24h. Microscopic analysis showed extensive branching and maturation of vessel-like structures in 7 days. Western blot and flow cytometry analysis showed that this process is accompanied by the acquisition of classical endothelial markers, CD34 and VE-cadherin. More importantly, we show that this process is VEGF-independent, but IKKbeta-dependent. Our findings suggest that anti-angiogenic therapies should take into consideration the inherent capacity of these cells to serve as vascular progenitors.