Combinatorial therapeutic approaches are an imperative to improve cancer treatment, because it is critical to impede compensatory signaling mechanisms that can engender drug resistance to individual targeted drugs. Currently approved drug combinations result largely from empirical clinical experience and cover only a small fraction of a vast therapeutic space. Here we present a computational network biology approach, based on pathway cross-talk inhibition, to discover new synergistic drug combinations for breast cancer treatment. In silico analysis identified 390 novel anticancer drug pairs belonging to 10 drug classes that are likely to diminish pathway cross-talk and display synergistic antitumor effects. Ten novel drug combinations were validated experimentally, and seven of these exhibited synergy in human breast cancer cell lines. In particular, we found that one novel combination, pairing the estrogen response modifier raloxifene with the c-Met/VEGFR2 kinase inhibitor cabozantinib, dramatically potentiated the drugs' individual antitumor effects in a mouse model of breast cancer. When compared with highthroughput combinatorial studies without computational prioritization, our approach offers a significant advance capable of uncovering broad-spectrum utility across many cancer types.Cancer Res; 77(2); 459-69. Ó2016 AACR.

A key element to delineate the biology of individual tumors is the regulation of apoptosis. In this work, we functionally characterize two breast cancer associated genes, the proteasome 26S subunit ATPase 3 interacting protein (PSMC3IP) and the epithelial-stromal interaction 1 (EPSTI1), to explore their potential apoptotic role in breast cancer. We first explore the existence of direct physical interactions with annotated BC-apoptotic genes. Based on the generated interaction network, we examine several apoptotic markers to determine the effect of PSMC3IP and EPSTI1 gene expression modulation in two different human breast cancer cell lines to suggest potential molecular mechanisms to unveil their role in the disease. Our results show that PSMC3IP and EPSTI1 are able to modulate the extrinsic apoptotic pathway in estrogen receptor positive and triple negative breast cancer cell lines, highlighting them as potential therapeutic targets.

BackgroundHyaluronic acid (HA), a naturally occurring polysaccharide, is used in the production of dermal fillers for esthetic purposes. As it has a few days of half-life in human tissues, HA-based dermal filler is chemically modified to increase its lifetime in the body. The most common modification used in commercial HA-based filler is the cross-linking of HA chains using 1,4-butanediol diglycidyl ether (BDDE) as cross-linking agent. Residual, or unreacted, BDDE is considered nontoxic when it is <2 parts per million (ppm); therefore, the quantification of residual BDDE in the final dermal filler is mandatory to ensure the safety of the patients.Materials and methodsThe present study describes the detection and characterization of one by-product of the cross-linking reaction between BDDE and HA in alkaline conditions by combining both liquid chromatography and mass spectroscopy (LC–MS).ResultsAfter different analyses, it was found that the alkaline conditions and the high temperatures employed to sterilize the HA–BDDE hydrogel promote the formation of this new by-product, a “propene glicol-like” compound. LC–MS analysis confirmed that this by-product have the same monoisotopic mass as that of BDDE, a different retention time (tR), and also a different UV absorbance (λ=200 nm) pattern. Unlike BDDE, it was observed in the LC–MS analysis that this by-product had a higher detection at 200 nm in the same assay conditions.ConclusionThese results suggest that this new compound does not have an epoxide on its structure. The discussion is open to assess the risk of this new by-product found in the production of HA–BDDE hydrogels (HA dermal fillers) for commercial purposes.

Mesotherapy/biorevitalization with hyaluronic acid (HA) is a treatment approach currently used for skin rejuvenation. Various products with a wide range of polycomponent formulations are available on the market. Most of these formulations contain noncross-linked HA in combination with a biorevitalization cocktail, formed by various amounts of vitamins, minerals, amino acids, nucleotides, coenzymes, and antioxidants. Although ingredients are very similar among the different products, in vitro and clinical effects may vary substantially. There is a real need for better characterization of these products in terms of their action on human skin or in vitro skin models. In this study, we analyzed the effect of the RRS® (Repairs, Refills, Stimulates) HA injectable medical device on human skin fibroblasts in vitro. Skin fibroblast viability and its capacity to induce the production of key extracellular matrix were evaluated in the presence of different concentrations of RRS HA injectable. Viability was evaluated through colorimetric MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and key extracellular matrix genes, type I collagen and elastin, were quantified by quantitative polymerase chain reaction. Results demonstrated that RRS HA injectable could promote human skin fibroblast viability (+15%) and increase fibroblast gene expression of type I collagen and elastin by 9.7-fold and 14-fold in vitro, respectively. These results demonstrate that mesotherapy/biorevitalization products can, at least in vitro, effectively modulate human skin fibroblasts.

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