Natural products targeting into cancer hallmarks: An update on caffeine, theobromine, and (+)-catechin.

Natural products have been studied to reveal new therapies against human dysfunctions since they present several medicinal properties. Caffeine, theobromine and (+)-catechin are remarkable natural agents in the class of methylxanthines and flavonoids. These bioactive molecules have several biological activities, for instance, antioxidant, anti-inflammatory, and antitumor capacity. In this sense, studies focusing on these molecules have been performed to discover new treatments against diseases, such as cancer. Cancer is a serious public health problem worldwide responsible for more than 70% of all deaths globally. Industrialized products associated with a sedentary lifestyle and a diet low in antioxidants are related to neoplasms development. Unfortunately, many types of cancers are extremely aggressive and untreatable since, in many cases, they are resistant to chemotherapy. Therefore, revealing new strategies to block cancer growth is one of the biggest challenges to science. In this context, despite the known anticancer actions of caffeine, theobromine and (+)-catechin, it is still essential to elucidate the causal antitumor mechanism of these molecules by analyzing the dysfunctional cancer pathways associated with the hallmarks of cancer. Hence, this review aims to describe the anticancer activity of caffeine, theobromine, and (+)-catechin against the different hallmarks and enabling characteristics of cancer.

Guaraná, a Highly Caffeinated Food, Presents in vitro Antitumor Activity in Colorectal and Breast Cancer Cell Lines by Inhibiting AKT/mTOR/S6K and MAPKs Pathways.

The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPKs) pathways are frequently upregulated in cancer. Some authors have reported that some antioxidant molecules could be potential inhibitors of these pathways. Therefore, we investigated the in vitro antitumor effect of guaraná by inhibiting the AKT/mTOR/S6K and MAPKs pathways. Colorectal and breast cancer cell lineages, HT-29 and MCF-7 cells, respectively, were exposed to different guaraná concentrations (0.1, 1, 10, and 100 µg/mL) as well as its main bioactive molecule, caffeine, in proportional concentrations to those found in the extract. Western blot, clonogenic assay, and growth curve were performed. Moreover, we investigated the potential cytotoxic effect of guaraná in normal cells. The results revealed that guaraná and caffeine inhibited some MAPKs proteins (p-p38 and p-HSP27) in MCF-7 cells. However, they did not affect this pathway in HT-29 cells. Furthermore, guaraná inhibited mTORC1 (p-S6K) and mTORC2 (p-AKT) in MCF-7 cells, but only mTORC1 in HT-29 cells. Caffeine only inhibited the mTOR pathway in MCF-7 cells. Guaraná decreased the colony formation and cell growth in MCF-7 and HT-29 cells. Guaraná did not affect normal cells. In conclusion, guaraná could be an important agent in antitumor pharmacologic therapies by inhibiting the mTOR and MAPKs pathways.

Lemongrass (Cymbopogon citratus (D.C.) Stapf) Presents Antitumoral Effect and Improves Chemotherapy Activity in Prostate Cancer Cells.

BACKGROUND: Prostate cancer is the most common visceral neoplasia in men and frequently presents chemotherapy resistance. In this context, lemongrass (Cymbopogon citratus (D.C.) Stapf) has been studied since it presents many important biological activities, such as anticancer. OBJECTIVE: We investigated the antitumor effect of lemongrass and in chemotherapy activity using prostate cancer cells line (DU-145). METHODS: DU-145 cells were exposed to different concentrations of aqueous extract of lemongrass (30; 100; 300; 500 and 1000 µg/mL), isolated and in combination with docetaxel, during 24 and 72 hours. After, cell viability and proliferation, oxidative metabolism, colony formation and cell cycle analyses were performed. Also, we exposed the African green monkey kidney cell line (VERO) to the same lemongrass concentrations to investigate a possible toxicity of this extract. RESULTS: Our findings suggested that lemongrass presented an antitumor effect and improved docetaxel chemotherapy activity by decreasing cell viability and proliferation as well as colony formation. Moreover, we found an oxidative stress increased and cell cycle arresting in G0 /G1 phase. In addition, this extract presented selectivity action for cancer cells, since it did not cause cytotoxicity in normal cells, ensuring non-toxic therapeutic concentrations. CONCLUSION: Lemongrass is a promising medicinal plant that could be used during chemotherapeutic treatment, in order to potentiate the antitumor response and decrease the resistance of prostate cancer.

Açaí (Euterpe oleracea Mart.) reduces the inflammatory response triggered in vitro by the antipsychotic drug olanzapine in RAW 264.7 macrophage cells.

BACKGROUND: Açaí (Euterpe oleracea Mart), a Brazilian fruit, is considered a "superfruit" due its energetic properties and bioactive compounds. The açai's anti-inflammatory effects could attenuate the undesirable metabolic and pro-inflammatory side effects triggered by some antipsychotic drugs, such as Olanzapine (OLZ). It is possible to infer that açai supplement could potentially minimize the adverse effects of OLZ. Aim. This study tested the potential in vitro effects of açai hydroalcoholic extract on the inflammatory activation of the RAW 264.7 macrophage line triggered by OLZ antipsychotic drugs. METHODS: An in vitro protocol was performed using commercial RAW 264.7 macrophages, cultured under sterile conditions at 37°C with 5% CO2 saturation. Initially, a pharmacological curve was defined to determine the concentration of Olanzapine to be used. After this, the cells were supplemented with different concentrations of hydroalcoholic extract of açaí, which had been previously chemically characterized. After 24 and 72 hours of treatment, oxidative and inflammatory tests were performed. Therefore, the aim of this study was to verify whether the hydroalcoholic extract of açaí can modulate the oxy-inflammatory response of olanzapine in vitro. RESULTS: From a preliminary analysis, the açai extract at 5 mg/mL presented higher activity against inflammation triggered by OLZ (0.03 µg/mL). At this concentration, açai was able to reduce several oxidative and inflammatory markers triggered by OLZ (0.03 µg/mL) exposure, such as nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1b, IL-6, TNF-a, IFN-g) caused by OLZ (0.03 µg/mL). Moreover, açaí reverted the levels of anti-inflammatory cytokine IL-10 that had been dropped by OLZ exposure to their pre-exposure treatments. CONCLUSIONS: The results suggest that açai extract could be useful in attenuating the peripheral inflammatory states triggered by OLZ. Additional pre-clinical and clinical investigations could be useful in testing therapeutic açai extract supplements.

Cytotoxic effects of moderate static magnetic field exposure on human periphery blood mononuclear cells are influenced by Val16Ala-MnSOD gene polymorphism.

Technological advancement has increasingly exposed humans to magnetic fields (MFs). However, more insights are necessary into the potential toxicity of MF exposure as a result of genetic variations related to oxidative metabolism. Therefore, the following study has assessed an in vitro cytotoxic effect of static magnetic field (SMF) (5 mT) on cells with Val16Ala polymorphism (AA, VA, and VV) in the manganese superoxide dismutase gene. Homozygous Val16Ala-superoxide dismutase 2 (SOD2) genotypes present oxidative imbalance that is associated with risk to several chronic degenerative diseases (VV produces less efficient and AA more efficient SOD2 enzyme). Blood samples from healthy adult subject carriers with different Val16Ala-SOD2 genotypes were obtained and exposed to MF at different times (0, 1, 3, 6 h). The cytotoxic effect as well as oxidative stress was evaluated after incubation of 24 h at 37 °C. In addition, apoptosis induction has been analyzed by flow cytometry as well as Bcl-2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and caspases 8 and 3 gene expression. SMF cytotoxic effect has been observed in AA cells at all times of exposure, whereas AV cells presented higher mortality only after 6 h of exposure at SMF. Higher apoptosis induction has been observed in AA cells when compared to VV and AV cells. These results suggest a toxicogenetic SMF effect related to an imbalance in SOD2 activity.

Effect of Uncaria tomentosa Extract on Apoptosis Triggered by Oxaliplatin Exposure on HT29 Cells.

Background/Aim. The use of herbal products as a supplement to minimize the effects of chemotherapy for cancer treatment requires further attention with respect to the activity and toxicity of chemotherapy. Uncaria tomentosa extract, which contains oxindole alkaloids, is one of these herbal products. The objective of this study was to evaluate whether Uncaria tomentosa extract modulates apoptosis induced by chemotherapy exposure. Materials and Methods. Colorectal adenocarcinoma cells (HT29 cells) were grown in the presence of oxaliplatin and/or Uncaria tomentosa extract. Results. The hydroalcoholic extract of Uncaria tomentosa enhanced chemotherapy-induced apoptosis, with an increase in the percentage of Annexin positive cells, an increase in caspase activities, and an increase of DNA fragments in culture of the neoplastic cells. Moreover, antioxidant activity may be related to apoptosis. Conclusion. Uncaria tomentosa extract has a role for cancer patients as a complementary therapy. Further studies evaluating these beneficial effects with other chemotherapy drugs are recommended.