Ricardo Teixo

Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation.

Immune surveillance seems to represent an effective tumor suppressor mechanism. However, some cancer cells survive and become variants, being poorly immunogenic and able to enter a steady-state phase. These cells become functionally dormant or remain hidden clinically throughout. Neoplastic cells seem to be able to instruct immune cells to undergo changes promoting malignancy. Radiotherapy may act as a trigger of the immune response. After radiotherapy a sequence of reactions occurs, starting in the damage of oncogenic cells by multiple mechanisms, leading to the immune system positive feedback against the tumor. The link between radiotherapy and the immune system is evident. T cells, macrophages, Natural Killer cells and other immune cells seem to have a key role in controlling the tumor. T cells may be dysfunctional and remain in a state of T cell exhaustion, nonetheless, they often retain a high potential for successful defense against cancer, being able to be mobilized to become highly functional. The lack of clinical trials on a large scale makes data a little robust, in spite of promising information, there are still many variables in the studies relating to radiation and immune system. The clarification of the mechanisms underlying immune response to radiation exposure may contribute to treatment improvement, gain of life quality and span of patients.

Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine fused chlorins as very active photodynamic agents for melanoma cells.

The development of new stable 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins with high absorption properties at 650 nm, and their impressive photosensitizer ability against melanotic and amelanotic cancer cells is described. Comparison between a diester-substituted chlorin with the corresponding dihydroxymethyl derivative demonstrated that the increased hydrophilicity of the latter is crucial to ensure nanomolar activity against melanoma cells. The new photosensitizer leads to death of human melanoma cells being both apoptosis and necrosis in equal parts involved in the treatment response. The dihydroxymethyl-chlorin was particularly active against human melanocytic melanoma A375 cells, which can be viewed as a solution to overcome the resistance of melanotic melanoma to photodynamic therapy.

Molecular Targets in Lung Cancer Therapy: A Current Review

Lung cancer presents a heterogeneous nature, which became more and more evident. Generally this type of cancer in an advanced state has a poor prognosis. The discovery of multiple molecular mechanisms, associated to the development, proliferation and prognosis of lung cancer has created new opportunities for a targeted therapy, improving clinical results. Non-small cells lung cancer is characterized by mutations on Epidermal Growth Factor Receptor and/or in the signaling pathways related to this receptor, which promoted the development of selective monoclonal antibodies and Epidermal Growth Factor Receptor-Tirosine Kinase Inhibitors, blocking the proliferation, differentiation, angiogenesis and tumor survival. Thus, our review highlighted the importance of a continuous research of new molecular targets in lung cancer to achieve better therapeutic outcomes and overall survival rates.

Beyond the limits of oxygen: effects of hypoxia in a hormone-independent prostate cancer cell line.

Prostate cancer (PCa) has a high incidence worldwide. One of the major causes of PCa resistance is intratumoral hypoxia. In solid tumors, hypoxia is strongly associated with malignant progression and resistance to therapy, which is an indicator of poor prognosis. The antiproliferative effect and induced death caused by doxorubicin, epirubicin, cisplatin, and flutamide in a hormone-independent PCa cell line will be evaluated. The hypoxia effect on drug resistance to these drugs, as well as cell proliferation and migration, will be also analyzed. All drugs induced an antiproliferative effect and also cell death in the cell line under study. Hypoxia made the cells more resistant to all drugs. Moreover, our results reveal that long time cell exposure to hypoxia decreases cellular proliferation and migration. Hypoxia can influence cellular resistance, proliferation, and migration. This study shows that hypoxia may be a key factor in the regulation of PCa.

Biosimilar medicines - Review.

INTRODUCTION By definition, biosimilars are similar to a biological reference that has already received marketing authorization for biologic drugs.The purpose of biosimilars is reducing costs, thus increasing access to this treatment, however, the concerns of health professionals and users refer to the fact that to reduce costs will not neglecting the quality, effectiveness and especially security. OBJECTIVE The aim of this study is then to assess the degree of similarity between the biosimilar and its reference biopharmaceuticals, trying to understand the production process, requirements necessary for approval, and its impact on the quality, safety, efficacy and costs. METHODS For the systematic review without meta-analysis, we researched articles to the b-on, Pubmed and Medscape to 2005-2014, and selected 23 articles that contributed to the verification of the objectives of this study. RESULTS Several studies indicate that overall the biosimilar and biological reference showed no significant differences except those inherent to the production process, being the first susceptible to comparability tests demonstrating the similarity in terms of clinical efficacy and safety. CONCLUSION Biosimilars will be increasingly present in the future as promising therapeutic arsenal and targeted therapy, however, issues related to immunogenicity, interchangeability, automatic substitution and extrapolation of indications should continue to be studied and debated.

Radiotherapy Effects on Immune System of Patients with Solid and Hematopoietic Tumors

Background: Radiotherapy (RT) recruits biological effectors outside the treatment field with systemic effects. Non-cancerous cells surrounding the tumor may play a pivotal role in cancer progression, as well as in metastasis. Local radiation triggers systemic effects, which in combination with immunotherapy may contribute to better treatment outcomes. Objective: The aim of this study was to evaluate RT effects on peripheral immune system (IS) in patients with lung cancer (LC) or diffuse large B cell lymphoma (DLBCL) after external beam radiotherapy. Methods: We studied a group of LC and DLBCL patients immediately before RT (T0), half-treatment (T1) and 30 days after the end of treatment (T2). Blood samples were analyzed by flow cytometry for CD3, CD4, CD8, CD19, CD56, CD25, CD127 FoxP3 expression. Procarta Cytokine Profiling kit was used to quantify cytokines and chemokines concentrations. Results: In LC patients, a decrease in B, Natural Killer (NK) and cytotoxic NK cells were observed during treatment, associated with an increase of interleukin (IL)-27 and IL-7 from T0 to T1 and followed by a decrease at T2. DLBCL patients showed increased levels of induced regulatory T cells from T1 to T2 and interferon gamma (INF-γ) over time. Comparing the two pathologies, we perceived that LC patients had increased cell subpopulation levels of IL-1β, IL-2, INF-γ, IL-5 and chemokine (C-C motif) ligand 5 compared to DLBCL patients. Conclusions: RT induces different IS responses between LC and DLBCL patients. Generally, the IS status of the patients at the beginning of the treatment can contribute to different RT treatment responses.

PO-269 Targeting aldh inhibition in endometrial cancer cells

Introduction Endometrial carcinoma is the most common malignancy of the female genital tract in developed countries. These tumours, usually are early diagnosed and associated to a good prognosis, although 20% of the cases, present an aggressive and invasive behaviour. Cancer stem cells (CSC) are defined as an undifferentiated tumour cell subpopulation involved in tumour initiation, resistance to therapy and metastatic phenotype. Several mechanisms are associated to resistance to therapy, such as pathways of aldehyde dehydrogenase (ALDH), an enzyme related with tumour size, lymphatic nodal invasion, recurrent disease, and poor prognosis. In endometrial cancer, the ALDH1 expression was related to tumorigenesis and chemoresistance. In our previous work, ALDH expression was associated with endometrial CSC phenotype. Material and methods RL95-2, a human endometrial cancer cell line, was submitted to ALDH inhibitors, diethylaminobenzaldehyde (DEAB) 50–100 µM, all-trans retinoic acid (ATRA) 5–10 µM and JQ1 100–250 nM for 48 hours. The cytotoxicity was evaluated through MTT assay. ALDH expression was evaluated through western blot. Sphere formation assay was performed, cells were cultured in coated plates with poly(2-hydroxyethyl-methacrylate), with serum-free DMEM F12 medium with or without 100 µM DEAB, for 5 days. Every two days, spheres were supplemented with EGF and bFGF at a concentration of 10 ng/mL. To evaluate the sphere projection area, spheres obtained were photographed at a magnification of 400x and analysed with Image J software. Results and discussions The metabolic activity in of RL95-2 cells was not influenced by the presence of ALDH inhibitors. Cells submitted to 50 and 100 µM DEAB presented a decrease in ALDH relative expression compared with the control cells, of about 36% and 27%, respectively. Regarding the evaluation of sphere projection area, preliminary results showed that spheres submitted to 100 µM DEAB appears to harbour decreased dimensions than control spheres. Conclusion DEAB was the most promising ALDH inhibitor in endometrial cancer cells. This inhibitor also seems to influence the sphere profile considering spheres dimensions. In further studies, we aim to evaluate its influence in the response to cytostatics. Funding FCT (Portugal) PEst-UID/NEU/04539/2013 and FEDER-COMPETE (FCOMP-01–0124-FEDER-028417 and POCI-01–0145-FEDER-007440), Bolsa Liga Portuguesa Contra o Cancro/CIMAGO, CIMAGO n° 02/2017, Sociedade Portuguesa de Ginecologia/Bayer.