Unusual dimeric flavonoids (brachydins) induce ultrastructural membrane alterations associated with antitumor activity in cancer cell lines.

Notwithstanding the advances in molecular target-based drugs, chemotherapy remains the most common cancer treatment, despite its high toxicity. Consequently, effective anticancer therapies with fewer adverse effects are needed. Therefore, this study aimed to determine the anticancer activity of the dichloromethane fraction (DCMF) isolated from Arrabidae brachypoda roots, whose components are three unusual dimeric flavonoids. The toxicity of DCMF was investigated in breast (MCF-7), prostate (DU145), and cervical (HeLa) tumor cells, as well as non-tumor cells (PNT2), using sulforhodamine B (cell viability), Comet (genotoxicity), clonogenicity (reproductive capacity) and wound healing (cell migration) assays, and atomic force microscopy (AFM) for ultrastructural cell membrane alterations. Molecular docking revealed affinity between albumin and each rare flavonoid, supporting the impact of fetal bovine serum in DCMF antitumor activity. The IC50 values for MCF7, HeLa, and DU145 were 2.77, 2.46, and 2.51 µg/mL, respectively, and 4.08 µg/mL for PNT2. DCFM was not genotoxic to tumor or normal cells when exposed to twice the IC50 for up to 24 h, but it inhibited tumor cell migration and reproduction compared to normal cells. Additionally, AFM revealed alterations in the ultrastructure of tumor nuclear membrane surfaces, with a positive correlation between DCMF concentration and tumor cell roughness. Finally, we found a negative correlation between roughness and the ability of DCMF-treated tumor cells to migrate and form colonies with more than 50 cells. These findings suggest that DCFM acts by causing ultrastructural changes in tumor cell membranes while having fewer toxicological effects on normal cells.

Marine-Derived Penicillium purpurogenum Reduces Tumor Size and Ameliorates Inflammation in an Erlich Mice Model.

BACKGROUND: This study addresses the antitumoral properties of Penicillium purpurogenum isolated from a polluted lagoon in Northeastern Brazil. METHODS: Ethyl Acetate Extracellular Extract (EAE) was used. The metabolites were studied using direct infusion mass spectrometry. The solid Ehrlich tumor model was used for antitumor activity. Female Swiss mice were divided into groups (n = 10/group) as follows: The negative control (CTL-), treated with a phosphate buffered solution; the positive control (CTL+), treated with cyclophosphamide (25 mg/kg); extract treatments at doses of 4, 20, and 100 mg/kg; animals without tumors or treatments (Sham); and animals without tumors treated with an intermediate dose (EAE20). All treatments were performed intraperitoneally, daily, for 15 days. Subsequently, the animals were euthanized, and the tumor, lymphoid organs, and serum were used for immunological, histological, and biochemical parameter evaluations. RESULTS: The extract was rich in meroterpenoids. All doses significantly reduced tumor size, and the 20 and 100 mg/kg doses reduced tumor-associated inflammation and tumor necrosis. The extract also reduced the cellular infiltration of lymphoid organs and circulating TNF-α levels. The extract did not induce weight loss or renal and hepatic toxic changes. CONCLUSIONS: These results indicate that P. purpurogenum exhibits immunomodulatory and antitumor properties in vivo. Thus, fungal fermentation is a valid biotechnological approach to the production of antitumor agents.

Could Increased Expression of Hsp27, an "Anti-Inflammatory" Chaperone, Contribute to the Monocyte-Derived Dendritic Cell Bias towards Tolerance Induction in Breast Cancer Patients?

Dendritic cells (DCs) are the most efficient antigen-presenting cells and link the innate immune sensing of the environment to the initiation of adaptive immune responses, which may be directed to either acceptance or elimination of the recognized antigen. In cancer patients, though DCs would be expected to present tumor antigens to T lymphocytes and induce tumor-eliminating responses, this is frequently not the case. The complex tumor microenvironment subverts the immune response, blocks some effector mechanisms, and drives others to support tumor growth. Chronic inflammation in a tumor microenvironment is believed to contribute to the induction of such regulatory/tolerogenic response. Among the various mediators of the modulatory switch in chronic inflammation is the "antidanger signal" chaperone, heat shock protein 27 (Hsp27), that has been described, interestingly, to be associated with cell migration and drug resistance of breast cancer cells. Thus, here, we investigated the expression of Hsp27 during the differentiation of monocyte-derived DCs (Mo-DCs) from healthy donors and breast cancer patients and evaluated their surface phenotype, cytokine secretion pattern, and lymphostimulatory activity. Surface phenotype and lymphocyte proliferation were evaluated by flow cytometry, interferon- (IFN-) γ, and interleukin- (IL-) 10 secretion, by ELISA and Hsp27 expression, by quantitative polymerase chain reaction (qPCR). Mo-DCs from cancer patients presented decreased expression of DC maturation markers, decreased ability to induce allogeneic lymphocyte proliferation, and increased IL-10 secretion. In coculture with breast cancer cell lines, healthy donors' Mo-DCs showed phenotype changes similar to those found in patients' cells. Interestingly, patients' monocytes expressed less GM-CSF and IL-4 receptors than healthy donors' monocytes and Hsp27 expression was significantly higher in patients' Mo-DCs (and in tumor samples). Both phenomena could contribute to the phenotypic bias of breast cancer patients' Mo-DCs and might prove potential targets for the development of new immunotherapeutic approaches for breast cancer.

Prevalence of human papillomavirus infection in squamous cell carcinoma of the anal canal in a Northeast City in Brazil: viral genotyping and clinical aspects

Background: Anal cancer malignancies comprise about 1.5 to 3% of cancers from the gastrointestinal in which high-risk types of human papillomavirus (HR-HPV) is responsible for >80% of cases. The aim of this work was to detect and perform human papillomavirus (HPV) genotyping in squamous cell carcinoma specimens from the anal canal and to investigate the association between viral infection and histopathological and clinical aspects. Methods: The presence of genotype-specific HPV DNA in formalin-fixed paraffin embedded tissue from 27 anal SCC samples from a reference cancer hospital of São Luís, State of Maranhão, Brazil was performed by Linear Array HPV Genotyping Test and the INNO-LiPA HPV Genotyping Assay. Fisher's Exact test and Chi-square test were performed in order to evaluate the association between HPV type and clinical and morphological variables. P values less than 0.05 were considered statistically significant. Results: Average age of patients at the time of diagnosis was 54.96 years ± 15.81; 74.07% of patients were female. Vegetative ulcers represented the most common type of lesion (22.22%). The lesions ranged in size from 2.1 cm to 5.0 cm and mostly were well-differentiated (70.38%). Lymph node involvement was observed in 26% of the patients. Molecular evaluation revealed that HPV infection was detected in 81.48% of the lesions, and the most common type found was the oncogenic HPV 16. Statistical analysis indicated that the clinical and histopathological variables were not associated with HPV infection. Conclusions: Our results indicate that anal SCC rarely occurs in the absence of HPV and emphasize the predominant role of HPV16. The evaluation about genotype-specific prevalence of HPV in anal SCC is important to assess the potential benefit of HPV vaccination (AU)