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Abstract: Phytochemicals are being used for thousands of years to prevent dreadful malignancy. Side effects of existing allopathic treatment have also initiated intense research in the field of bioactive phytochemicals. Gallic acid, a natural polyphenolic compound, exists freely as well as in polymeric forms. The anti-cancer properties of gallic acid are indomitable by a variety of cellular pathways such as induction of programmed cell death, cell cycle apprehension, reticence of vasculature and tumor migration, and inflammation. Furthermore, gallic acid is found to show synergism with other existing chemotherapeutic drugs. Therefore, the antineoplastic role of gallic acid suggests its promising therapeutic candidature in the near future. The present review describes all these aspects of gallic acid at a single platform. In addition nanotechnology-mediated approaches are also discussed to enhance bioavailability and therapeutic efficacy.

VAL-083 (Dianhydrogalactitol) is a bi-functional DNA targeting agent that is currently being evaluated in a phase II trial in recurrent glioblastoma (GBM) patients. The goal of the present study was to further elucidate the anti-neoplastic effects and signaling pathways through which VAL-083 functions. We examined the efficacy of VAL-083 against a panel of eight GBM stem cells (GSCs) isolated from newly diagnosed GBM patients. The panel of GSCs were molecularly phenotyped based on the expression of several proteins including EGFR, EGFRvIII, and MGMT as well as several stem cell markers including SOX2, NESTIN, MST1, CD133, TFRC, and OLIG2. The effect of VAL-083 on GSC growth was measured using WST-1 reagent and the effect on GSC’s ability to form neurospheres was assessed by microscopy. Our results show that VAL-083 inhibits neurosphere formation in all eight GSCs. Further, VAL-083 inhibits the growth of GSCs with an IC(50) of 200–2000 nM. To identify the molecular pathways affected by VAL-083, control and VAL-083-treated GSCs were subjected to proteomic analysis using reverse phase protein array (RPPA) technology. The RPPA examined the expression of a total of 297 proteins and phosphoproteins. It was found that VAL-083 affects the expression of several proteins and phosphoproteins central to GBM growth. A key protein significantly downregulated by VAL-083 was bromodomain protein 4 (BRD4). This is a salient important finding because BRD4 has been implicated in several cancers including GBM, and agents that target BRD4 are undergoing development as anti-neoplastic agents. In summary, we report that VAL-083 is effective in halting the growth of a panel of GSC isolated from newly diagnosed GBM patients and the underlying mechanism involves downregulation of BRD4.

Intrinsic and acquired resistance to conventional and targeted therapeutics is a fundamental reason for treatment failure in many cancer patients. Targeted approaches to overcome chemoresistance as well as resistance to targeted approaches require in depth understanding of the underlying molecular mechanisms. The anti-cancer activity of a drug can be limited by a broad variety of molecular events at different levels of drug action in a cell-autonomous and non-cell-autonomous manner. This review summarizes recent insights into the adaptive mechanisms used by tumours to resist therapy including cellular phenotypic plasticity, dynamic alterations of the tumour microenvironment, activation of redundant signal transduction pathways, modulation of drug target expression levels, and exploitation of pro-survival responses. Fundacao para a Ciencia e Tecnologia (FCT) [SFRH/BPD/100434/2014] Research Center Grant Centre for Biomedical Research [UID/BIM/04773/2013, 1334] Norwegian Research Council Norwegian Cancer Society and Helse Vest Health Authority ProRegem grant [PD/BD/114258/2016] Info:eu-repo/semantics/publishedVersion

Anticancer drugs, interfering with DNA in every living organism, may pose a threat to aquatic environment, even more when they occur as complex mixtures. We investigated the combined long term toxic potential of four anti-neoplastic drugs (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET] and imatinib mesylate [IM]) testing their binary mixtures on two primary consumers of the freshwater aquatic chain with close phylogenetic relationship: Daphnia magna and Ceriodaphnia dubia . The combined toxicities were assessed using two distinct effect sizes that should be observed if Bliss independence holds. Direct statistical comparison by analysis of variance of single and combined toxicities under the assumption of Bliss independence allowed to accept or reject the independency hypothesis. Independency was confirmed for all mixtures both in D. magna and in C. dubia , except for IM+ ET and IM + CDDP in D. magna and for ET + CDDP and ET + 5-FU in C. dubia which at the highest concentrations showed an antagonistic interaction. A synergic tendency was found testing IM + CDDP on C. dubia at the lowest concentration selected. Thus, the chronic ecotoxicological data evaluated in this study show not only a potential environmental risk of anticancer drugs, especially considering their potential synergistic effects, but also the necessity to integrate statistical models with experimental data to establish the real environmental impact of such compounds.

Over the past several years, there have been a number of relevant evidence-based randomized trials that have the potential to change the standard management paradigm in the malignancy of ovarian cancer and (most importantly) enhance clinically relevant outcomes. This commentary will briefly review these trials.