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

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

Molecular structure of DM-1.

<p>Molecular structure of DM-1.</p

Involvement of apoptotic members in melanoma tissues samples of B16F10 melanoma-bearing mice.

<p>Protein total extracts were used to analyzed Bcl-2, Bax, caspase-8, caspase-9 and caspase-3 after DTIC, DTIC+DM-1 or DM-1 treatment at the endpoint of the experiment. α-Tubulin expression was used as a loading control.</p

Liver (A); lungs (B); kidneys (C) and spleen (D) weight of untreated normal mice and B16F10 melanoma-bearing mice after DTIC, DM-1 or DTIC+DM-1 treatment.

<p>The values are expressed as mean ± s.d. Significance is indicated by #p<0.05 compared to untreated normal mice.</p

Macroscopic aspect of B16F10 melanoma-bearing mice on the 7^th, 10^th and 14^th days of treatment with DTIC, DM-1 or DTIC+DM-1 in comparison to control group.

<p>The measurements were made using a caliper rule.</p

Total weight and tumor mass of B16F10 melanoma-bearing mice on the 1st day of DTIC, DM-1 or DTIC+DM-1 treatment in comparison to the control group (A); Total weight and tumor mass of B16F10 melanoma-bearing mice on the 7^th day of DTIC, DM-1 or DTIC+DM-1 treatment in comparison to the control group(B); Total weight and tumor mass of B16F10 melanoma-bearing mice on the 14^th day of DTIC, DM-1 or DTIC+DM-1 treatment in comparison to the control group (C).

<p>The values are expressed as mean ± s.d. Significance is indicated by *p<0.05, **p<0.01 and ***p<0.001 compared to control.</p

Red blood cells (RBC) (A); reticulocytes (B); white blood cells (WBC) (C) and platelets (D) in peripheral blood of untreated normal mice and B16F10 melanoma-bearing mice after DTIC, DM-1 or DTIC+DM-1 treatment.

<p>The peripheral blood was collected and the cells were counted on the 1st, 7th and 14th days of treatment. The values are expressed as mean ± s.d. Significance is indicated by: *p<0.05, **p<0.01 and ***p<0.001 compared to control; and #p<0.05, ##p<0.01 and ###p<0.001 compared to untreated normal mice.</p

New antitumoral agents I: in vitro anticancer activity and in vivo acute toxicity of synthetic 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one and derivatives

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 IC50 values ⩽2.3 μM for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate181762756281CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPnão tem2004/11351-0; 2006/00116-

The curcumin analog DM-1 induces apoptotic cell death in melanoma

The 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. Cell death was evaluated by flow cytometry for annexin V and iodide propide, cleaved caspase 8, and TNF-R1 expression. Hoechst 33342 staining was evaluated by fluorescent microscopy; lipid peroxidation and cell viability (MTT) were evaluated by colorimetric assays. The antiproliferative effects of the drugs were evaluated by flow cytometry for cyclin D1 and Ki67 expression. Mice bearing B16F10 melanoma were treated with DTIC, DM-1, or both therapies. DM-1 induced significant apoptosis as indicated by the presence of cleaved caspase 8 and an increase in TNF-R1 expression in melanoma cells. Furthermore, DM-1 had antiproliferative effects in this the same cell line. DTIC caused cell death primarily by necrosis, and a smaller melanoma cell population underwent apoptosis. DTIC induced oxidative stress and several physiological changes in normal melanocytes, whereas DM-1 did not significantly affect the normal cells. DM-1 antitumor therapy in vivo showed tumor burden decrease with DM-1 monotherapy or in combination with DTIC, besides survival rate increase. 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