Current Cancer Drug Targets - Volume 14, Issue 8, 2014

AML with Mt NPM1 has relatively good responses to induction therapy. However, a proportion of NPMc+ AML cells cannot be cleared by conventional treatments. Therefore, we determined the therapeutic efficacy of deguelin that has demonstrated extensive biological activity with low toxicity. We previously reported that deguelin selectively reduces Mt NPM1, as well as induces differentiation and potentiates apoptosis in NPMc+ AML cells. Nevertheless, little information is available regarding the mechanism of deguelin-induced differentiation. Here, we investigated the role of deguelin in the induction of NPMc+ AML cell differentiation. Deguelin at the nontoxic concentration of 2 μM strongly inhibited cell growth but reduced apoptosis in OCI-AML3 cells carrying Mt NPM1, whereas the antiproliferative effect was minimal in OCIM2 cells harboring Wt NPM1. Compared with OCIM2 cells that showed no response, deguelintreated OCI-AML3 cells exhibited the morphological features of granulocytic/monocytic differentiation, increased expression of differentiation antigens, and a nitroblue tetrazolium reduction activity. Induction of differentiation was associated with downregulation of Mt NPM1 and SIRT1, but not Wt NPM1, which was accompanied by an increase in CEBPβ and G-CSFR expression, and further confirmed by sh-Mt NPM1 and sh-SIRT1. sh-Mt NPM1 treatment reduced SIRT1 expression, but did not change HDAC1/3 levels, suggesting that the decline of SIRT1 was partially accountable for the deguelin-induced, Mt-NPM1-related differentiation. Moreover, Mt NPM1 overexpression blocked deguelin-induced cell differentiation. Lastly, we showed that deguelin reduced the expression of Mt NPM1 via the ubiquitin-proteasome pathway. Taken together, our results suggest that deguelin may be a therapeutic candidate for NPMc+ AML.

Cell survival in chronic lymphocytic leukemia (CLL) largely depends on B-cell receptor-induced AKT activation. Gain-of-function genomic lesions of PI3K-AKT-mTOR pathway components are usually absent in CLL. We previously established that a BCR-mediated growth response in CLL is determined by the oncogene T-cell leukemia 1 (TCL1) through a sensitizer effect on AKT phospho-activation. Despite high clinical response rates following AKTcascade inhibition in CLL, resistances in a substantial proportion of patients call for reliable pre- and post-exposure strata to better predict compound responses. Using a panel of inhibitors with differential vertical affinities in the PI3K-AKTmTOR axis, we describe distinct patterns and determinants of sensitivities in 75 CLL samples. The compounds specifically impacted the BCR-induced physical TCL1-AKT interaction. In general, there was an efficient and tumorselective abrogation of cell survival in suspension or protective stromal-cell cultures. However, biochemical and survival responses were heterogeneous across CLL and showed only incomplete overlap across inhibitors. Sensitivity clusters could be defined by differential responses to selective pan-PI3K inhibition vs. compounds acting more down-stream. An elevated PI3K/AKT/mTOR activation state conferred sensitivity or resistance, depending on the applied inhibitor. In fact, down-stream interception by mTOR or dual mTOR/PI3K inhibition appears more efficient in cases expressing the BCRresponse and poor-risk determinants of ZAP70 or TCL1. Finally, exploiting the TCL1-AKT interaction, peptide-based TCL1-interphase mimics were potent in steric AKT antagonization and in reducing CLL cell survival. Overall, this study provides informative response relationships in AKT-pathway interception that can help refining predictive models in BCR-pathway inhibition in CLL.

This review systematically examines the literature and data on the prognostic significance of heat shock proteins (heat shock protein - Hsp) Hsp27, Hsp60, Hsp70, Hsp90 in various cancers. Our analysis of the literature showed that the existing data are contradictory with regard to the prognostic significance of Hsp. This result may be due to biological differences of the carcinomas studied and methodological differences in the assessment of heat shock proteins. Heat shock proteins play a significant role in the development of cancer, as they are highly expressed and thus allow tumor cells to escape apoptotic death. Therefore, the inhibition of Hsps is currently an attractive potential therapeutic approach against cancer.

Metformin, a biguanide, is a commonly administered drug for the management of type 2 diabetes mellitus. The drug received tremendous recognition, when retrospective studies proved metformin-associated reduction in cancer risk. Metformin has potential anticancer effects and an ability to suppress tumor growth both in vitro and in vivo. Activation of LKB1/AMPK pathway and cancer stem cell destruction along with cell cycle arrest and apoptosis induction are the proposed mechanisms of anticancer potential of metformin. Nanotechnology approaches have also been adopted for metformin delivery to cancer cells. This review directs on the application of metformin for the therapy of various cancers and also the different pathways responsible for the metformin derived anticancer effect. It also focuses on the pharmacological applications of metformin and the nanotechnology approaches for metformin delivery.

Altered expression of the microRNA-34 family has been determined to be involved in the pathogenesis of many cancers. In this review, the current knowledge of the cancer-related mechanisms in relation to the modulatory effects of microRNA-34 family were analysed. Expression analysis of the microRNA-34 family has suggested that its members play significant roles in many aspects of cancer biology including proliferation, invasion/metastasis, apoptosis/cell survival, cell cycle/cell growth, migration, senescence/aging, angiogenesis, epigenetic silencing and methylation by regulation of the expression of their target genes. Thus, microRNA-34 family members could act as prognostic markers and therapeutic targets in human cancers.

Proteins are posed as the natural counterpart of the synthetic polymers for the development of drug delivery systems and few of them, have been regarded safe for drug delivery purposes by the United States Food and Drug Administration (FDA). Serum albumin is the most abundant protein in human blood. Interest in the exploration of pharmaceutical applications of albumin-based drug delivery carriers, especially for the delivery of chemotherapeutic agents, has increased in recent years. Albumin has several advantages over synthetic polymers, as it is biocompatible, biodegradable, has low cytotoxicity and has an excellent binding capacity with various drugs. Micro- and nano-carriers not only protect active pharmaceutical ingredients against degradation, but also offer a prolonged release of drugs in a controlled fashion. Since existing tumour chemotherapeutic agents neither target tumour cells, nor are they specific to tumour cells, a slow release of drugs from carriers would be beneficial in targeting carcinogenic cells intracellularly. This article aims at providing an overview of pharmaceutical applications of albumin as a drug delivery carrier in tumour chemotherapy.

Targeted therapy, the treatment of cancer based on an underlying genetic alteration, is rapidly gaining favor as the preferred therapeutic approach. To date, although natural products represent a rich resource of bio-diverse drug candidates, only a few have been identified to be effective as targeted cancer therapies largely due to the incompatibilities to current high-throughput screening methods. In this article, we review the utility of a zebrafish developmental screen for bioactive natural product-based compounds that target signaling pathways that are intimately shared with those in humans. Any bioactive compound perturbing signaling pathways identified from phenotypic developmental defects in zebrafish embryos provide an opportunity for developing targeted therapies for human cancers. This model provides a promising tool in the search for targeted cancer therapeutics from natural products.