Abstract
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.
Highlights
Skin cancer is the most common human cancer worldwide and melanoma is a highly aggressive form of this cancer
The cytotoxic effects were obtained with DM-1 compound administered alone or in combination with chemotherapeutic DTIC
The group treated with DM-1 compound alone and the group treated with both therapies showed 57% and 63% tumor burden reduction, respectively, compared to the control group
Summary
The B16F10 murine melanoma cell line was purchased from the American Type Culture Collection (Manassas, USA). The cells were grown in 75 cm flasks with DMEM medium (Cultilab, Brazil) supplemented with 10% heat-inactivated fetal bovine serum (Cultilab, Brazil), 2 mM L-glutamine (Sigma Chemical Company, USA) and 0.1 g/mL streptomycin (FontouraWyeth AS, USA) at 37°C in a 5% CO2 atmosphere. Dried sodium ethanolate (0.01 mol) was mixed with 1,5-bis(4-hydroxy-3-methoxyphenyl)1,4-pentadien-3-one [11] (0.01 mol; 3.26 g) in a 1:1 molar ratio and stirred at room temperature under anhydrous reaction conditions, followed by solvent rotoevaporation until solidification. The compound C19H17O5Na has a molecular weight of 348g (Fig. 1). Results of the structural characterization of the isolated compound were the same as those described previously by our group [12,13]
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