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Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression.

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.

SUBMITTER: Faiao-Flores F

PROVIDER: S-EPMC4350837 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression.

Faião-Flores Fernanda F Quincoces Suarez José Agustín JA Fruet Andréa Costa AC Maria-Engler Silvya Stuchi SS Pardi Paulo Celso PC Maria Durvanei Augusto DA

PloS one 20150305 3

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 ...[more]

PMID: 25742310

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Project description:Skin hyperpigmentation disorders arise due to excessive production of the macromolecular pigment melanin catalyzed by the enzyme tyrosinase. Recently, the therapeutic use of curcumin for inhibiting tyrosinase activity and production of melanin have been recognized, but poor stability and solubility have limited its use, which has inspired synthesis of curcumin analogs. Here, we investigated four novel chemically modified curcumin (CMC) derivatives (CMC2.14, CMC2.5, CMC2.23 and CMC2.24) and compared them to the parent compound curcumin (PC) for inhibition of in vitro tyrosinase activity using two substrates for monophenolase and diphenolase activities of the enzyme and for diminution of cellular melanogenesis. Enzyme kinetics were analyzed using Lineweaver-Burk and Dixon plots and nonlinear curve-fitting to determine the mechanism for tyrosinase inhibition. Copper chelating activity, using pyrocatechol violet dye indicator assay, and antioxidant activity, using a DPPH radical scavenging assay, were also conducted. Next, the capacity of these derivatives to inhibit tyrosinase-catalyzed melanogenesis was studied in B16F10 mouse melanoma cells and the mechanisms of inhibition were elucidated. Inhibition mechanisms were studied by measuring intracellular tyrosinase activity, cell-free and intracellular α-glucosidase enzyme activity, and effects on MITF protein level and cAMP maturation factor. Our results showed that CMC2.24 showed the greatest efficacy as a tyrosinase inhibitor of all the CMCs and was better than PC as well as a popular tyrosinase inhibitor-kojic acid. Both CMC2.24 and CMC2.23 inhibited tyrosinase enzyme activity by a mixed mode of inhibition with a predominant competitive mode. In addition, CMC2.24 as well as CMC2.23 showed a comparable robust efficacy in inhibiting melanogenesis in cultured melanocytes. Furthermore, after removal of CMC2.24 or CMC2.23 from the medium, we could demonstrate a partial recovery of the suppressed intracellular tyrosinase activity in the melanocytes. Our results provide a proof-of-principle for the novel use of the CMCs that shows them to be far superior to the parent compound, curcumin, for skin depigmentation.

Project description:BackgroundAlthough uveal melanoma (UM) at the early stage is controllable to some extent, it inevitably ultimately leads to death due to its metastasis. At present, the difficulty is that there is no way to effectively tackle the metastasis. It is hypothesized that these will be treated by target molecules, but the recognized target molecule has not yet been found. In this study, the target molecule was explored through proteomics.MethodsTransgenic enhanced green fluorescent protein (EGFP) inbred nude mice, which spontaneously display a tumor microenvironment (TME), were used as model animal carriers. The UM cell line 92.1 was inoculated into the brain ventricle stimulating metastatic growth of UM, and a graft re-cultured Next, the UM cell line 92.1-A was obtained through monoclonal amplification, and a differential proteomics database, between 92.1 and ectopic 92.1-A, was established. Finally, bioinformatics methodologies were adopted to optimize key regulatory proteins, and in vivo and in vitro functional verification and targeted drug screening were performed.ResultsCells and tissues displaying green fluorescence in animal models were determined as TME characteristics provided by hosts. The data of various biological phenotypes detected proved that 92.1-A were more malignant than 92.1. Besides this malignancy, the key protein p62 (SQSTM1), selected from 5267 quantifiable differential proteomics databases, was a multifunctional autophagy linker protein, and its expression could be suppressed by chloroquine and dacarbazine. Inhibition of p62 could reduce the malignancy degree of 92.1-A.ConclusionsAs the carriers of human UM orthotopic and ectopic xenotransplantation, transgenic EGFP inbred nude mice clearly display the characteristics of TME. In addition, the p62 protein optimized by the proteomics is the key protein that increases the malignancy of 92.1 cells, which therefore provides a basis for further exploration of target molecule therapy for refractory metastatic UM.

Dataset Information

Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression.

Publications

Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression.

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