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Anti-cancer agents in medicinal chemistry [journal]
- Brca1 As Target For Breast Cancer Prevention And Therapy. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Oct 20.
The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer.
- Different 6-Aryl-Fulvenes exert anti-proliferative effects on Cancer Cells. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Oct 19.
Fulvenes represent a class of molecules very interesting under a chemical point of view because are easily accessible starting materials and are still poorly characterized for their biological activities, with the exception of acylfulvene and irofulvenes which have been reported to exert cytotoxic properties. Here, we describe the synthesis and characterization of several aryl-fulvenes together with their effects on cancer cell growth by MTT method. The cytotoxic potential was investigated on a panel of tumor cell lines such as breast MCF7 and SkBr3, endometrial Ishikawa, prostate LnCaP and lung A549, in comparison with the cis-diamminedichloroplatinum(II) (cisplatin) which is largely used for the treatment of different types of cancer. The evaluation of the cytotoxic activity of these compounds indicated that they are able to inhibit the proliferation of the aforementioned cancer cell types. In particular, the compound 4 exhibited the most powerful antiproliferative activity on all tumor cells evaluated with higher inhibitory effects respect to cisplatin and without altering the proliferation of human mammary MCF-10A epithelial cells.
- Neoadjuvant strategies for triple negative breast cancer: 'state-of-the-art' and future perspectives. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Oct 19.
Neoadjuvant therapy for triple negative breast cancer (TNBC) has recently generated growing interest given the more aggressive biologic characteristics of such subtype and the lack of approved targeted therapies. Systemic chemotherapy represents the mainstay of treatment for TNBC. Although neoadjuvant chemotherapy has consistently demonstrated higher response rates for TNBC compared to non-TNBC, and the pathological complete response predicts long-term outcome, most patient display residual disease with a higher risk of relapse. In order to improve the outcome of TNBC new chemotherapic combinations, including platinum agents, and different targeted agents such as antiangiogenetics, poly-ADP ribose polymerase (PARP) inhibitors and other small molecule inhibitors are being evaluated in neoadjuvant setting. Currently, the research is ongoing to further characterize TNBC from a phenotypical and molecular perspective, in order to identify potential new target agents and to individualize the treatment. In this regard, the neoadjuvant setting may represent the best potential scenario to assess the activity and the sensitivity of novel agents.
- Molecular markers of angiogenesis and metastasis in lines of oral carcinoma after treatment with melatonin. [Journal Article]
- Anticancer Agents Med Chem 2014; 14(9):1302-11.
Oral cancer is the most common type of head and neck cancer and its high rate of mortality and morbidity is closely related to the processes of angiogenesis and tumor metastasis. The overexpression of the pro-angiogenic genes, HIF-1α and VEGF, and pro-metastatic gene, ROCK-1, are associated with unfavorable prognosis in oral carcinoma. Melatonin has oncostatic, antiangiogenic and antimetastatic properties in several types of neoplasms, although its relationship with oral cancer has been little explored. This study aims to analyze the expression of the genes HIF-1α, VEGF and ROCK-1 in cell lines of squamous cell carcinoma of the tongue, after treatment with melatonin.SCC9 and SCC25 cells were cultured and cell viability was assessed by MTT assay, after treatment with 100 μM of CoCl2 to induce hypoxia and with melatonin at different concentrations. The analysis of quantitative RT-PCR and the immunocytochemical analysis were performed to verify the action of melatonin under conditions of normoxia and hypoxia, on gene and protein expression of HIF-1α, VEGF and ROCK-1.The MTT assay showed a decrease in cell viability in both cell lines, after the treatment with melatonin. The analysis of quantitative RT-PCR indicated an inhibition of the expression of the pro-angiogenic genes HIF-1α (P < 0.001) and VEGF (P < 0.001) under hypoxic conditions, and of the pro-metastatic gene ROCK-1 (P < 0.0001) in the cell line SCC9, after treatment with 1 mM of melatonin. In the immunocytochemical analysis, there was a positive correlation with gene expression data, validating the quantitative RT-PCR results for cell line SCC9. Treatment with melatonin did not demonstrate inhibition of the expression of genes HIF-1α, VEGF and ROCK-1 in line SCC25, which has different molecular characteristics and greater degree of malignancy when compared to the line SCC9.Melatonin affects cell viability in the SCC9 and SCC25 lines and inhibits the expression of the genes HIF-1α, VEGF and ROCK-1 in SCC9 line. Additional studies may confirm the potential therapeutic effect of melatonin in some subtypes of oral carcinoma.
- Effect of two Antiandrogens as Protectors of Prostate and Brain in a Huntington´s Animal Model. [Journal Article]
- Anticancer Agents Med Chem 2014; 14(9):1293-301.
The purpose of this work is to know the effect of flutamide and a novel synthetic steroid 3β-p-Iodobenzoyloxypregnan-4,16- diene-6,20-dione (IBP) on the levels of dopamine, 5-HIAA (5-hydroxyindole acetic acid), and some oxidative stress markers in animal model with Huntington disease. Thirty male Wistar rats divided in groups of 6 animals each were subjected to the following treatment: group A, 3-nitro propionic acid (3-NPA, as inducer of Huntington); group B, flutamide; group C, 3-NPA + flutamide; group D, IBP; and group E, 3-NPA + IBP. Treatment scheme for all groups were at 4 mg/kg/day administered intraperitoneally. The measurement of haemoglobin was carried out from blood while the concentrations of ATPase, 5α-reductase, reduced glutathione (GSH), calcium, H2O2, 5-HIAA, and dopamine were determined from brain and prostate tissues using validated methods. The results depicted a significant decrease of dopamine and GSH in cerebellum/Medulla oblongata of animals treated with IBP. The prostate gland of the same group of treatment also showed a significant decrease in the concentrations of TBARS, H2O2, and total ATPase. In hemispheres of groups D and E, dopamine, H2O2, and total ATPase decreased significantly while in prostate, hemispheres, and cerebellum/Medulla oblongata of groups B and C; calcium, 5α-reductase, ATPase, H2O2, and TBARS were found to witness a significant decrease. Results showed an antiandrogenic activity of flutamide, while the novel steroid IBP showed neuroprotective properties by changes on oxidative stress biomarkers as critical pathways leading to prostate and brain degeneration. Probably steroid homeostasis disequilibrium could have led to alterations in dopamine metabolism GSH in Huntington´s disease animal models.
- Chalcones Incorporated Pyrazole Ring Inhibit Proliferation, Cell Cycle Progression, Angiogenesis and Induce Apoptosis of MCF7 Cell Line. [Journal Article]
- Anticancer Agents Med Chem 2014; 14(9):1282-92.
A Series of chalcone derivatives containing pyrazole ring was prepared and their cytotoxicity against different human cell lines, including breast (MCF-7), colon (HCT-116) liver (HEPG2) cell lines, as well as normal melanocyte HFB4 was evaluated. Two of these chalcone derivatives with different IC50 and chemical configuration were chosen for molecular studies in detail with MCF-7 cells. Our data indicated that the two compounds prohibit proliferation, angiogenesis, cell cycle progression and induce apoptosis of breast cancer cells. This inhibition is mediated by up regulation of tumor suppressor p53 associated with arrest in S-G2/M of cell cycle. This work provides a confirmation of antitumor activity of the novel chalcones and assists the development of new agents for cancer treatment.
- Toxic effects of Aflatoxin B1 on embryonic development of zebrafish (Danio rerio): Potential activity of Piceatannol encapsulated Chitosan/poly (lactic acid) nanoparticles. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Oct 16.
The aim was to analyse the efficacy of piceatannol (PIC) loaded chitosan (CS)/poly(lactic acid)(PLA) nanoparticles (CS/PLA-PIC NPs) in zebra fish embryos exposed to aflatoxin B1 (AFB1). FTIR confirmed the chemical interaction between the polymers and drug. SEM showed the size of CS/PLA-PIC NPs approximately 87 to 200nm, compared to CS-PLA NPs of 150nm size. The size was further affirmed as 127nm (CS-PLA NPs) and 147nm (CS/PLA-PIC NPs) by zetasizer depiction. CS/PLA-PIC NPs have not illustrated toxicity at high concentrations when tested in zebrafish embryos. AFB1 wielded its toxic effects on the survival, spontaneous movement, hatching and heart rate, and development of embryos were observed in both time and dose-dependent manner at 4µM. Our results suggested that the addition of CS/PLA-PIC NPs increases the survival, heart rate and hatching in time dependent manner at the dosage of 20µg/ml. These hopeful results may prompt the advancement of drug encapsulated polymeric nanoparticles which may have the potential role in improving the AFB1 induced toxicity in humans as well.
- Using Cytochalasins to Improve Current Chemotherapeutic Approaches. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Oct 16.
Although the amount of progress cancer therapy has made in recent years is commendable, considerable limitations still remain. Most agents preferentially target rapidly proliferating cells, thereby destroying tumorigenic growths. Unfortunately, there are many labile cells in the patient that are also rapidly dividing, ultimately perpetuating significant side effects, including immunosuppression. Cytochalasins are microfilament-directed agents most commonly known for their use in basic research to understand cytoskeletal mechanisms. However, such agents also exhibit profound anticancer activity, as indicated by numerous in vitro and in vivo studies. Cytochalasins appear to preferentially damage malignant cells, as shown by their minimal effects on normal epithelial and immune cells. Further, cytochalasins influence the end stages of mitosis, suggesting that such agents could be combined with microtubule-directed agents to elicit a profound synergistic effect on malignant cells. Therefore, it is likely cytochalasins could be used to supplement current chemotherapeutic measures to improve efficacy rates, as well as decrease the prevalence of drug resistance in the clinical setting.
- Synthesis, preferentially hypoxic apoptosis and anti-angiogenic activity of 1,2,4-benzotrazin-3-amine 1,4-dioxide bearing alkyl linkers with 1,2,4-benzotrazin-3-amine 1-oxide derivatives. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Oct 14.
3-(Aminoalkylamino)-1,2,4-benzotriazine 1,4-dioxide-extended derivatives were carried out by structural modifications of 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) that incorporated the homologue-alkyl linkers further with or without an extended 1,2,4-benzotrazin-3-amine 1-oxide moiety at 3-position of TPZ. After sequentially evaluated for preferentially normoxic and hypoxic cytotoxicities against MCF-7, NCI-H460 and HCT-116, most of the synthesized compounds showed more potent hypoxic cytotoxicity than or comparable to that of TPZ. Among them, compound 9a and 9b were more potent inhibitory proliferation of MCF-7, NCI-H460 and HCT-116 in hypoxia than that of TPZ. The representative 9a showed the most potent hypoxic cytotoxicity in comparison to TPZ, mediated by cell cycle arrest, induction of DNA damage, activation of caspase 3/7 and the cleaved poly(ADP-ribose) polymerase-related apoptosis, which were conducted at HCT-116 cells in both normoxia and hypoxia, respectively. In vitro anti-angiogenic assay of co-cultured HUVECs and fibroblasts exposed to the selected 7b, 8g, 9a and 9b had 80-90% inhibition of tube formation at 20 μM, whereas TPZ inhibited about 50% tube formation at 20 μM. At 2 μM, 9a and 9b still had significant decrease in area, length, path and joint of tube formation of 70-80% and 45-50%, respectively. These results indicated that TPZ derivatives were more potent anti-angiogenesis.
- Chrysin Induces Apoptosis in Peripheral Blood Lymphocytes Isolated from Human Chronic Lymphocytic leukemia. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Sep 24.
Chronic lymphocytic leukemia (CLL) develops due to an imbalance between apoptosis and proliferation of B lymphocytes. Chrysin induced apoptosis in leukemia cell lines such as U937, MO7e, THP-1 and HL-60, but there has not yet been data demonstrating the apoptotic effect of chrysin on CLL cells. Therefore, in our investigation we examined the cytotoxicity of chrysin against two leukemia cell lines, MOLT-4 and JVM-13, peripheral blood lymphocytes isolated from B-CLL patients and peripheral blood mononuclear cells (PBMC) from healthy individuals in vitro. The effect of chrysin on viability of MOLT-4 and JVM-13 cell lines, B-CLL cells derived from 28 patients and PBMC from 16 healthy subjects was determined by MTT assay. The type of cell death induced by chrysin was verified by Annexin V/7AAD assay and acridine orange and ethidium bromide (AO/EB) staining assay. Intracellular localisation and endogenic expression of apoptotic proteins including Bax, Bcl-2, cytochrome c and caspase-3 were determined by flow cytometry and fluorescent microscopy. Our results demonstrated that exposure of MOLT-4, JVM-13 cell lines and B-CLL cells to the concentration of chrysin of 10μM and higher selectively decreased viability of cells in this cell population, but not in the PBMC derived from healthy subjects; LC50 values of chrysin for B-CLL cells were 51μM for 24 hours and 32μM for 48 hours of incubation, respectively. Our findings demonstrated that chrysin induced the activation of proapoptotic Bax and decrease in the expression of antiapoptotic Bcl-2 protein, release of cytochrome c from mitochondria into cytosol and cleavage/activation of caspase-3, subsequently leading to the activation of apoptosis of B-CLL cells. Together, these findings suggest that chrysin selectively induces apoptosis of peripheral blood lymphocytes isolated from human chronic lymphocytic leukemia patients via mitochondrial pathway in vitro and that it might have a promising role as a potential future antileukemic remedy.