metabolic approach to the enhancement of antitumor effect of chemotherapy a key role of acetyl l carnitine

Purpose: Acetyl-l-carnitine (ALC) plays a relevant role in energy metabolism and stress response because of its function in the complex metabolic system regulating the acetyl-CoA levels that provide a source of acetyl groups for metabolic and acetylation-regulated processes. Because acetylation may influence p53 activity/stability and, therefore, the response to platinum compounds, this study was designed to investigate the effect of ALC in combination with platinum compounds. Experimental Design: The antiproliferative and antitumor activity studies were done in a panel of human tumor cell lines with functional or defective p53. The antimetastatic drug efficacy was investigated in the s.c. growing H460/M tumor subline, which is able to generate lung metastases. Results: ALC enhanced the sensitivity to cisplatin of tumor cells with functional p53. The sensitization by ALC was reflected in an improved in vivo antitumor efficacy of the combination over cisplatin alone in wild-type p53 lung tumors. ALC did not increase the cisplatin efficacy in the p53-mutant SW620 tumor. ALC exhibited a significant antimetastatic activity, and this effect was better exploited in combination with the histone deacetylase inhibitor, ST3595. The in vivo ALC/cisplatin combination caused the activation of p53, associated with protein acetylation and induction of target genes. Conclusions: ALC was effective in enhancing the antitumor potential of platinum compounds in wild-type p53 tumors. ALC, alone and in combination with a histone deacetylase inhibitor, exhibited an outstanding antimetastatic activity. Both effects, likely mediated by protein acetylation, may have implications for platinum-based therapy and combinations with histone deacetylase inhibitors. Clin Cancer Res; 16(15); 3944–53. ©2010 AACR

Characterization of Early and Late Damage in a Mouse Model of Pelvic Radiation Disease

Pelvic radiation disease (PRD), a frequent side effect in patients with abdominal/pelvic cancers treated with radiotherapy, remains an unmet medical need. Currently available preclinical models have limited applications for the investigation of PRD pathogenesis and possible therapeutic strategies. In order to select the most effective irradiation protocol for PRD induction in mice, we evaluated the efficacy of three different locally and fractionated X-ray exposures. Using the selected protocol (10 Gy/day x 4 days), we assessed PRD through tissue (number and length of colon crypts) and molecular (expression of genes involved in oxidative stress, cell damage, inflammation, and stem cell markers) analyses at short (3 h or 3 days after X-ray) and long (38 days after X-rays) post-irradiation times. The results show that a primary damage response in term of apoptosis, inflammation, and surrogate markers of oxidative stress was found, thus determining a consequent impairment of cell crypts differentiation and proliferation as well as a local inflammation and a bacterial translocation to mesenteric lymph nodes after several weeks post-irradiation. Changes were also found in microbiota composition, particularly in the relative abundance of dominant phyla, related families, and in alpha diversity indices, as an indication of dysbiotic conditions induced by irradiation. Fecal markers of intestinal inflammation, measured during the experimental timeline, identified lactoferrin, along with elastase, as useful non-invasive tools to monitor disease progression. Thus, our preclinical model may be useful to develop new therapeutic strategies for PRD treatment

Synthesis and evaluation of new Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold

Abstract: Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates, gave a new family of 1,4,5-trisubstitued triazole carboxylic acid derivatives that showed high affinity towards Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring, were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstitued triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18; SST0287CL1) was selected for further investigation as the most promising drug candidate

Investigating the relationship between women's entrepreneurship and country-level innovation: evidence from a panel of OECD countries

PurposeIn recent years, the topic of women's entrepreneurship has gained increasing attention from researchers and policymakers. Its role in economic growth and development has been widely recognized in several studies. However, the relationship between gender in entrepreneurship and innovation is an underexplored aspect in particular at a country-level perspective. This paper aims to answer the following question: Does female entrepreneurship impact innovation at a national level?Design/methodology/approachUsing a panel dataset of 35 Organization for Economic Co-operation and Development (OECD) member countries over the period 2002-2019, the authors carried out a comprehensive econometric analysis, based on the fixed-effect model, the random-effect model and the feasible generalized least squares estimator, as well as a battery of tests to prevent problems of multicollinearity, heteroscedasticity and autocorrelation of the error terms. In doing so, the authors found consistent and robust results on the linear and nonlinear relationship between women's entrepreneurship and innovation, using selected country indicators from the Global Entrepreneurship Monitor (GEM) consortium, the Worldwide Governance Indicators (WGI) and the World Development Indicators (WDI), including female self-employment, female nascent entrepreneurship and R&D investment and controlling for the same relationships in the case of men's entrepreneurship.FindingsThis study shows that the level of R&D investment, which according to the literature can be considered as a proxy of innovation, is higher when the level of women's entrepreneurship is low. However, exploring more in depth this relationship and the relationship between male entrepreneurship and innovation, the authors found two important and new results. The first one involves the different impact on R&D investment of female self-employment and female nascent entrepreneurship. In particular, female self-employment appears to have a linear negative impact on the R&D, while the impact of female nascent entrepreneurship is statistically nonsignificant. The second one affects the nonlinearity of the negative effect, suggesting that very different challenges are possible at different levels of women's entrepreneurship. In addition, analyzing the role of human capital in the relationship between R&D investment and women entrepreneurship, it emerges that higher education (as the main component of human capital) makes early-stage women's entrepreneurship more technologically consuming, which promotes R&D investment. A higher level of education lessens the significance of the negative relationship between the simplest type of women entrepreneurship (female self-employment) and R&D investment.Originality/valueThe originality of the study is that it provides new evidence regarding the link between women's entrepreneurship and innovation at the macro level, with a specific focus on self-employed women entrepreneurs and early-stage women entrepreneurship. In this sense, to the best of the authors' knowledge, this study is among the few showing a nonlinear relationship between women's entrepreneurship and country-level innovation and a negative impact only in the case of female self-employment. Moreover, this study has relevant implications from a policymaking perspective, in terms of promoting more productive women's entrepreneurship

A Novel Atypical Retinoid Endowed with Proapoptotic and Antitumor Activity

The novel atypical retinoid E-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid (ST1926) exhibited a potent antiproliferative activity on a large panel of human tumor cells. Despite almost complete loss of ability to activate RARs, the compd. was an effective apoptosis inducer and surprisingly produced DNA damage, that likely contributes to the proapoptotic activity. Following oral administration, 4 was well tolerated and caused tumor growth inhibition in the ovarian carcinoma, A2780/DX, and in the human melanoma, MeWo, growing in nude mice, thus supporting the therapeutic interest of the novel agent

Non-Natural Macrocyclic Inhibitors of Histone Deacetylases: Design, Synthesis, and Activity

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors

Synthesis and Evaluation of New Hsp90 Inhibitors Based on a 1,4,5-Trisubstituted 1,2,3-Triazole Scaffold

Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate