SummaryThe main difficulty in the successful treatment of metastatic melanoma is that this type of cancer is known to be resistant to chemotherapy. Chemotherapy remains the treatment of choice and dacarbazine (DTIC) is the best standard treatment. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor and antimetastatic properties. The objective of this study was to evaluate the signaling pathways involved in melanoma cell death after treatment with DM-1 compared to the standard agent for melanoma treatment, DTIC. Altogether, these data confirm DM-1 as a chemotherapeutic agent with effective tumor control properties and a lower incidence of side effects in normal cells compared to DTIC.

Malignant melanoma is a highly aggressive form of skin cancer with a high mortality rate if not discovered in early stages. Although a limited number of treatment options for melanoma currently exist, patients with a more aggressive form of this cancer frequently decline treatment. DM-1 is a sodium phenolate and curcumin analog with proven anticancer, anti-proliferative and anti-metastatic properties. In this paper, the DM-1 compound showed in vivo antitumor activity alone or in combination with chemotherapeutic DTIC in B16F10 melanoma-bearing mice. Beneficial effects such as melanoma tumor burden reduction with pyknotic nuclei, decreased nuclei/cytoplasmic ratio and nuclear degradation occurred after DM-1 treatment. No toxicological changes were observed in the liver, kidneys, spleen and lungs after DM-1 monotherapy or DTIC combined therapy. DTIC+DM-1 treatment induced the recovery of anemia arising from melanoma and immunomodulation. Both DM-1 treatment alone and in combination with DTIC induced apoptosis with the cleavage of caspase-3, -8 and -9. Furthermore, melanoma tumors treated with DM-1 showed a preferential apoptotic intrinsic pathway by decreasing Bcl-2/Bax ratio. Considering the chemoresistance exhibited by melanoma towards conventional chemotherapy drugs, DM-1 compound in monotherapy or in combination therapy provides a promising improvement in melanoma treatment with a reduction of side effects.

This paper describes a new method for the preparation of sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, DM-1, and 3-oxo-penta-1,4-dienyl-bis (2-methoxy-phenolate), DM-2. The aim of this work was to evaluate the antitumor effects of DM-1 in adjuvant chemotherapy for breast cancer treatment. Mice bearing mammary adenocarcinomas (Ehrlich ascites tumors) were treated with paclitaxel alone, DM-1 alone, and paclitaxel + DM-1. Tumor samples were used to perform cytological analysis by the Papanicolaou method and apoptosis analysis by annexin V and phosphorylated caspase 3. The paclitaxel + DM-1 group had decreased tumor areas and tumor volumes, and the frequency of metastasis was significantly reduced. This caused a decrease in cachexia, which is usually caused by the tumor. Furthermore, treatment with paclitaxel + DM-1 and DM-1 alone increased the occurrence of apoptosis up to 40% in tumor cells, which is 35% more than in the group treated with paclitaxel alone. This cell death was mainly caused through phosphorylated caspase 3 (11% increase in paclitaxel + DM-1 compared to the paclitaxel group), as confirmed by reduced malignancy criteria in the ascitic fluid. DM-1 emerges as a potential treatment for breast cancer and may act as an adjuvant in chemotherapy, enhancing antitumor drug activity with reduced side effects.

Melanoma is one of the most aggressive types of skin cancer and its incidence rate is still increasing. All existing treatments are minimally effective. Consequently, new therapeutic agents for melanoma treatment should be developed. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor and antimetastatic properties. The aim of this study was to evaluate the different signaling pathways involved in the cytotoxic effect of DM-1 on melanoma cells.The apoptotic process and cytoskeletal changes were evaluated by immunoblotting and immunofluorescence, respectively, in melanoma cells.After DM-1 treatment, SK-MEL-5 melanoma cells showed actin filaments disorganization with spicules formation throughout the cytoskeleton and significant reduction of focal adhesion as well as they were present only at cell extremities, conferring a poor connection between the cell and the substrate. Besides this, there was significant filopodium retraction and loss of typical cytoskeleton scaffold. These modifications contributed to cell detachment followed by cell death.Furthermore, DM-1-induced apoptosis was triggered by multiple Bcl-2 proteins involved in both the extrinsic and the intrinsic apoptotic pathways. SK-MEL-5 cells showed a death mechanism mainly by Bcl-2/Bax ratio decrease, whereas A375 cells presented apoptosis induction by Mcl-1 and Bcl-xL downregulation. In SK-MEL-5 and A375 melanoma cells, there were a significant increase in the active form of caspase 9 and the inactive form of the effector caspase 3 was decreased in both cell lines. Expression of cleaved Parp was increased after DM-1 treatment in these melanoma cell lines, demonstrating 2 that the apoptotic process occurred. Altogether, these data elucidate the cellular and molecular mechanisms involved in the cytotoxicity induced by the antitumor agent DM-1 in melanoma cells.

This paper describes a new method for the preparation of 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one 1 and its derivatives 2-5. This set of synthetic compounds exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines as lung carcinoma NCI-460, melanoma UACC-62, breast MCF-7, colon HT-29, renal 786-O, ovarian OVCAR-03 and ovarian expressing the resistance phenotype for adriamycin NCI-ADR/RES, prostate PC-3, and leukemia K-562. Compounds were also tested against murine tumor cell line B16F10 melanoma and lymphocytic leukemia L1210 as well as to their effect toward normal macrophages. Specific activity against colon cancer cells HT-29 was observed for all tested compounds and suggests further studies with models of colon cancer. Compounds 1, 2, and 4 showed significant cytotoxic activity with IC(50) values 2.3 microM for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate.

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Background: Hepatitis B virus (HBV) infections remain as a major health problem. It has been estimated that about 370 million people are chronically infected worldwide. Chronic infection also increases the risk of liver diseases such as cirrhosis and hepatocellular carcinoma. Current antiviral therapies fail to control viral replication in the long term. Viral persistence has EHHQ DVVRFLDWHG ZLWK D GHIHFW LQ WKH GHYHORSPHQW RI +%9VSHFL¿F cellular immunity. The limitations of the current available therapies underline the need for alternative therapies. The development of a HBV therapeutic vaccine still remains as a feasible option of treatment despite several drawbacks. Recently, approaches like adoptive T-cell therapy have been evaluated. Materials and methods:The adoptive transfer was done intraperitoneally using Balb/c mice as donors and HBsAg-WUDQVJHQLF PLFH DV UHFHSWRUV 7KH +%V$J FRQFHQWUDWLRQ VSHFL¿F IgG response and biochemical parameters was evaluated in transgenic mice sera by ELISA. The histopathological analysis of the main organs was carried out. Results and discussion:In the present work we demonstrated WKDW WKH DGRSWLYH WUDQVIHU RI +%9VSHFL¿F FHOOXODU LPPXQLW\ GLG QR cause histopathological damage. The potent immune response transferred was developed in non-Tg Balb/c mice after multiple simultaneous intranasal and subcutaneous immunizations with NASVAC, a novel HBV therapeutic vaccine candidate. The results indicated that the transference of immunity is safe and also capable of transiently reducing the HBsAg concentration in the sera of transgenic mice. These data support the safety of the therapeutic vaccination using NASVAC and also are in line with the usefulness of the T-cell therapy for chronic hepatitis B.

A series of ribofuranosyl-and 2-deoxyribofuranosyl homo-and spacered-C-nucleosides have been synthesized by reaction of fully protected 3-(1-deoxy-β-D-ribofuranosyl-1-yl)propanal (1), 3-(1,2-dideoxy-β-D-ribofuranos-1-yl)propanal (14), 1-(1-desoxy-β-D-ribofuranos-1-yl)pent-4-yn-3-on (19), 1-(1-desoxy-β-D-ribofuranos-1-yl)-5-phenyl-pent-4-yn-3-on (20), 1-(1,2-didesoxy-β-D-ribofuranos-1-yl)pent-4-yn-3-on (29), and 1-(1,2-didesoxy-β-D-ribofuranos-1-yl)-5-phenylpent-4-yn-3-on (30) with different nucleophiles. The preparation of 1 and 14 proceeds by Knoevenagel reaction with malononitrile, cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acetamide and subsequent cyclization with sulphur to thiophenes 5, 7, 8, 16 and then by cyclization with triethyl orthoformate to give thienopyrimidine 6 and thienopyrimidinone 9, 10, and 17. Treatment of acetylenic ketones 19, 20, 29, and 30 with acetamidinium chloride, benzamidinium chloride, and S-methylisothiouronium sulphate provided the corresponding pyrimidines 21-26, 31, 32. Finally, the use of 4H-1,2,4-triazol-3-amine and 2-aminobenzimidazole as 1,3-N,N'-dinucleophiles afforded the triazolopyrimidines 35, 39 and the pyrimidobenzimidazoles 36, 37, and 40, respectively. Deprotection of a selected number of Cnucleosides was achieved by one or two steps procedure without serious problems. That makes these C-nucleosides promising candidates for the synthesis of monomers suitable for solid phase nucleic acid oligomerization.