The additionally glycosylated variant of human sex hormone-binding globulin (SHBG) is linked to estrogen-dependence of breast cancer.

Summary Sex Hormone-Binding Globulin (SHBG), the plasma carrier for androgens and estradiol, inhibits the estradiolinduced proliferation of breast cancer cells through its membrane receptor, cAMP, and PKA. In addition, the SHBG membrane receptor is preferentially expressed in estrogen-dependent (ER+/PR+) breast cancers which are also characterized by a lower proliferative rate than tumors negative for the SHBG receptor. A variant SHBG with a point mutation in exon 8, causing an aminoacid substitution (Asp 327 → Asn) and thus, the introduction of an additional N-glycosylation site, has been reported. In this work, the distribution of the SHBG variant was studied in 255 breast cancer patients, 32 benign mammary disease patients, and 120 healthy women. The presence of the SHBG mutation was evaluated with PCR amplification of SHBG exon 8 and Hinf I restriction fragment length polymorphism (RFLP) procedure. This technique allowed us to identify 54 SHBG variants (53 W/v and 1 v/v) in breast cancer patients (21.2%), 5 variants (4 W/v and 1 v/v) in benign mammary disease patients (15.6%), and 14 variants (W/v) in the control group (11.6%). The results of PCR and RFLP were confirmed both by nucleotide sequence of SHBG exon 8 and western blot of the plasma SHBG. No differences in the mean plasma level of the protein were observed in the three populations. The frequency of the SHBG variant was significantly higher in ER+/PR+ tumors and in tumors diagnosed in patients over 50 years of age than in the control group. This observation suggests the existence of a close link between the estrogen-dependence of breast cancer and the additionally glycosylated SHBG, further supporting a critical role of the protein in the neoplasm

Extracorporeal shock waves enhance normal fibroblast proliferation in vitro and activate mRNA expression for TGF-β1 and for collagen types I and III

Background and purpose Extracorporeal shock waves (ESWs) are used to good effect in the treatment of soft tissue injuries, but the underlying mechanisms are still unknown. We therefore determined the effects of ESWs on normal fibroblasts in vitro, in order to assess treatment-induced cell response

Antiproliferative activity of Pyrrolo[3,2-c]quinoline derivatives

The pyrrolo[3,2-c]quinoline scaffold has been known as a core structure of a wide number of bioactive molecules. Several derivatives of such a tricyclic angular heterocycle have shown a wide spectrum of biological activities, such as hypotensive, anti-inflammatory properties, gastric (H)ATPase inhibition effect, and remarkable antitumor activity (1). The high therapeutic potentiality of such a skeleton along with our interest in targets featuring aza-polycondensed aromatic structures, attracted us to develop an alternative synthetic strategy, in order to reach a series of pyrrolo[3,2-c]quinolines in quantitative yields (2). The reaction of 3-acetyl-1,4-dione 1 with selected amines allowed the isolation of intermediates 2. Subsequent reduction of the nitro group and condensation with substituted aldehydes drove the cyclization to pyrrolo[3,2-c]quinoline ring system 3.Substituted pyrrolo[3,2-c]quinolines 3 were preliminary evaluated for antiproliferative activity (MTS assays) against 5 human tumor cell lines (colon tumor Caco2; breast cancer MCF7; brain cancer LAN5; cervix HeLa and lung tumor H292), and human epithelial bronchial cell line 16HBE as control. Moreover, benzomethylen-dioxy derivative tested at DTP/NCI showed an appreciable and selective cell growth inhibitory effect against Leukemia SR, Melanoma MDA-MB-435, Renal Cancer UO-31 cell lines

Exploring the anticancer potential of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives: The effect on apoptosis induction, cell cycle and proliferation

In order to investigate their anticancer potential, four new pyrazolo[1,2-a]benzo[1,2,3,4]tetrazinone derivatives, designed through the chemometric protocol VLAK, and three of the most active compounds of the previous series have been evaluated on some cellular events including proliferation, apoptosis induction, and cell cycle. The NCI one dose (10 μM) screening revealed that the 8,9-di-methyl derivative showed activity against Leukemia (CCRF-CEM) and Colon cancer cell line (COLO 205), reaching 81% and 45% of growth inhibition (GI), respectively. Replacement of the two methyl groups with two chlorine atoms maintained the activity toward Leukemia cell (CCRF-CEM, GI 77%) and selectively enhanced the activity against COLO 205 attaining a LD50 in the μM range and against SW-620 a GI of 77%. Interestingly, an appreciable growth inhibition of 47% against therapeutically "refractory" Non-Small Cell Lung Cancer (NCI-H522) was observed. Moreover, the apoptosis induction, based on mitochondrial membrane depolarization, was found in the range EC50 3-5 μM on HeLa cell, evidencing a well defined relationship with the related in vitro cell growth inhibitory assays (MTT) performed against other selected tumor cell lines not included in the NCI tumor panel (HeLa, cervix; H292, lung; LAN-5, CNS; CaCo-2, colon; 16HBE, normal human cell lung) and against MCF-7 tumor cell line (breast). Only for the most active compounds, further cell cycle tests on HeLa displayed a cell arrest on S phase. Thus, a promising new class of anticancer candidates, acting as valuable apoptotic inductors, is proposed

Synthesis and antiproliferative activity of Naphtalenyl substituted 1,2-dihydropyrazol-5-one and related fused tetrazine

In recent years, besides the main field of nonsteroidal anti-inflammatory agents, the interest towards pyrazolone derivatives has been renewed because of their wide biological and pharmacological applications [1]. Currently, particular attention is focused on such a class of compounds due to the affinity with sigma receptor and their relationship with cancer [2].To these purposes we planned to design, synthesize and evaluate the antiproliferative activity (MTS assays) of a new series of 3-methyl-2-(1-R-naphthalen-2-yl)-1,2-dihydropyrazol-3-one derivatives 1 against HeLa, MCF-7, LAN-5, Caco2 in order to explore their anticancer potential. Additionally, further elaboration of the amino derivative 1 led to the tetracycle 2, possessing a reactive tetrazinone core which conferred valuable antiproliferative activity as previously reported [3]. Synthesis and biological results will be presented. [1] G. Mariappan, B.P. Saha, L. Sutharson, Anki, S. Garg, L. Pandey, D. Kumar, J. Pharm. Res., 2010, 3(12), 2856. [2] E. Aydar, C.P. Palmer, M. B. A. Djamoz, Cancer Res., 2004, 64, 5029. [3] A.M., Almerico, F. Mingoia, P. Diana, P. Barraja, A. Lauria, A. Montalbano, G Cirrincione, G. Dattolo, J. Med. Chem., 2005, 48, 2859