Plant-Derived Bioactive Compounds in Colorectal Cancer: Insights from Combined Regimens with Conventional Chemotherapy to Overcome Drug-Resistance.

Acquired drug resistance represents a major clinical problem and one of the biggest limitations of chemotherapeutic regimens in colorectal cancer. Combination regimens using standard chemotherapeutic agents, together with bioactive natural compounds derived from diet or plants, may be one of the most valuable strategies to overcome drug resistance and re-sensitize chemoresistant cells. In this review, we highlight the effect of combined regimens based on conventional chemotherapeutics in conjunction with well-tolerated plant-derived bioactive compounds, mainly curcumin, resveratrol, and EGCG, with emphasis on the molecular mechanisms associated with the acquired drug resistance.

Breast Cancer-Delivered Exosomal miRNA as Liquid Biopsy Biomarkers for Metastasis Prediction: A Focus on Translational Research with Clinical Applicability.

Metastasis represents the most important cause of breast cancer-associated mortality. Even for early diagnosed stages, the risk of metastasis is significantly high and predicts a grim outcome for the patient. Nowadays, efforts are made for identifying blood-based biomarkers that could reliably distinguish patients with highly metastatic cancers in order to ensure a closer follow-up and a more personalized therapeutic method. Exosomes are nano vesicles secreted by cancer cells that can transport miRNAs, proteins, and other molecules and deliver them to recipient cells all over the body. Through this transfer, cancer cells modulate their microenvironment and facilitate the formation of the pre-metastatic niche, leading to sustained progression. Exosomal miRNAs have been extensively studied due to their promising potential as prognosis biomarkers for metastatic breast cancer. In this review, we tried to depict an overview of the existing literature regarding exosomal miRNAs that are already validated as potential biomarkers, and which could be immediately available for the clinic. Moreover, in the last section, we highlighted several miRNAs that have proven their function in preclinical studies and could be considered for clinical validation. Considering the lack of standard methods for evaluating exosomal miRNA, we also discussed the challenges and the technical aspects underlying this issue.

Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers.

Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets.

Pro-apoptotic genes as new targets for single and combinatorial treatments with resveratrol and curcumin in colorectal cancer.

Colorectal cancer (CRC) represents the third most diagnosed type of cancer worldwide with high mortality and an increased incidence rate. Bioactive dietary components such as curcumin and resveratrol have great therapeutic potential as they can modulate a plethora of signaling pathways related to colorectal carcinogenesis. Previous data have demonstrated that curcumin and resveratrol can induce apoptosis in different types of cancer cells. Considering the lack of data on the combinatorial effect of curcumin and resveratrol associated with the induction of apoptosis in colorectal pathology, the main objective of this study is to investigate the impact of single vs. combinatorial treatment of resveratrol and curcumin on their cytotoxic effects, as well as the modulation of several essential pro-apoptotic genes, on two colorectal cancer cell lines (DLD-1 and Caco-2) different in terms of chromosomal stability (MSI and MSS). The cytotoxic effects were evaluated by the MTT assay, the nature of the interaction between curcumin and resveratrol was assessed by the combination index method and the expression levels of key genes involved in the modulation of pro-apoptotic mechanisms were evaluated by RT-qPCR. Our data indicate that the combination treatment of curcumin and resveratrol is more effective in inhibiting the proliferation in a dose-dependent manner, with a synergistic effect for the DLD-1 cell line (CI < 1) and an additive effect for the Caco-2 cell line (CI ≥ 1). The IC50 values for the combination treatment were 71.8 µM (20.5 µM curcumin + 51.3 µM resveratrol) for the DLD-1 cell line and 66.21 µM (18.9 µM curcumin + 47.3 µM resveratrol) for the Caco-2 cell line, respectively. Our data pointed out, for the first time, that several genes involved in the modulation of apoptosis, including PMAIP1, BID, ZMAT3, CASP3, CASP7, and FAS, represent new targets of both singular and combinatorial treatments with resveratrol and curcumin, and also the combinatorial approach of curcumin and resveratrol exhibits a more powerful gene regulating effect compared to single treatment. Considering the beneficial aspects of the combinatorial approach with curcumin and resveratrol on colorectal cancer cells further studies should address the possible pharmacological benefits of using a combination of both dietary agents with different chemotherapeutic drug approaches.