Antitumor activity of bengamide ii in a panel of human and murine tumor cell lines: In vitro and in vivo determination of effectiveness against lung cancer

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.biopha.2023.115789We thank Instrumentation Scientific Center (CIC) from University of Granada for technical assistance and the FQM397 research group of the University of Malaga.Lung cancer is the most commonly diagnosed cancer and the one that causes the most deaths worldwide, so there is a need for therapies that improve survival rates. Products derived from marine organisms are a source of novel and potent antitumor compounds, but they present the great obstacle of their obtaining from the natural environment and the problems associated with the synthesis and biological effects of chemical analogues. In this work, a Bengamide analogue (Bengamide II) was chemically synthesized and in vitro and in vivo studies were performed to determine its antitumor activity and mechanisms of action. It was shown to have potent antiproliferative activity in lung cancer lines in 2D and 3D models. In addition, Bengamide II-treated cells showed G2/M and G0/G1 cell cycle arrest, together with a decrease in the proliferation marker Ki67. As for the mechanism of action, the treatment was associated with increased LC3-II expression and production of acidic vesicles signaling autophagy. In addition, Bengamide II treatment was associated with caspase-3 activation and DNA fragmentation related to apoptosis. Furthermore, a reduction of VEGFA expression, related to angiogenesis, was also observed. In vivo studies showed that Bengamide II markedly reduced tumor volume and metastases increasing survival. Additionally, it revealed no systemic toxicity in in vivo models at the therapeutic doses used, which is essential for its future clinical use. Taken together, the chemically synthesized bengamide analogue Bengamide II, is a promising drug for lung cancer treatment showing relevant antitumor activity and significant safety.Junta de Andalucía through project FP20_00540/FEDER and partially through the Projects A-CTS-666- UGR20 and RTI2018-098296-BI00 (MINECO and FEDER)CTS-107(Andalusian Government)FPU2020 grant (ref. FPU20/07083) from the Ministerio de Educación y Formación Profesional (Spain

Natural Products Derived from Marine Sponges with Antitumor Potential against Lung Cancer: A Systematic Review

Non-small-cell lung cancer (NSCLC), the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide, has been extensively investigated in the last decade in terms of developing new therapeutic options that increase patient survival. In this context, marine animals are a source of new, interesting bioactive molecules that have been applied to the treatment of different types of cancer. Many efforts have been made to search for new therapeutic strategies to improve the prognosis of lung cancer patients, including new bioactive compounds and cytotoxic drugs from marine sponges. Their antitumoral effect can be explained by several cellular and molecular mechanisms, such as modulation of the cell cycle or induction of apoptosis. Thus, this systematic review aims to summarize the bioactive compounds derived from marine sponges and the mechanisms by which they show antitumor effects against lung cancer, exploring their limitations and the challenges associated with their discovery. The search process was performed in three databases (PubMed, SCOPUS, andWeb of Science), yielding a total of 105 articles identified in the last 10 years, and after a screening process, 33 articles were included in this systematic review. The results showed that these natural sponge-derived compounds are a valuable source of inspiration for the development of new drugs. However, more research in this field is needed for the translation of these novel compounds to the clinic.Granada University (P20B-2023 from Programa del Plan Propio de Investigación

Extracellular vesicle-miRNAs as liquid biopsy biomarkers for disease identification and prognosis in metastatic colorectal cancer patients

We would like to extend our gratitude to the all the patients and the healthy volunteers who participated in the study, as well as the University of Granada, Biomedicine PhD program. This work was supported by Roche Spain, the PhD grant from the University of Granada (DdMP) (2014) and the PhD grant from the Spanish Government (ARM) (FPU) 2014, REF FPU14/05461.Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths. Addition of biological drugs, as Bevacizumab, to chemotherapy, has increased progression free survival and overall survival of metastatic colorectal cancer (mCRC) patients. However, these benefits have been only reported in a small proportion of patients. To date, there are not biomarkers that could explain the heterogeneity of this disease and would help in treatment selection. Recent findings demonstrated that microRNAs (miRNAs) play an important role in cancer and they can be encapsulated with high stability into extracellular vesicles (EVs) that are released in biological fluids. EVs can act as cell-to-cell communicators, transferring genetic information, such as miRNAs. In this context, we aimed to investigate serum EV associated miRNAs (EV-miRNAs) as novel non-invasive biomarkers for the diagnosis and prognosis of Bevacizumab-treated mCRC patients. We observed that baseline miRNA-21 and 92a outperformed carcinoembryonic antigen levels in the diagnosis of our 44 mCRC patients, compared to 17 healthy volunteers. In addition, patients who died presented higher levels of miRNA-92a and 222 at 24 weeks. However, in the multivariate Cox analysis, higher levels of miRNA-222 at 24 weeks were associated with lower overall survival. Altogether, these data indicate that EV-miRNAs have a strong potential as liquid biopsy biomarkers for the identification and prognosis of mCRC.Roche SpainUniversity of Granada (DdMP)Spanish Government REF FPU14/0546

Exchange of cellular components between platelets and tumor cells: impact on tumor cells behavior.

Background: Platelets are active players in tumorigenesis, although the exact interactive mechanisms and their direct impact on tumor cells remain largely unknown. Methods: Bidirectional transference of lipids, proteins and RNA between platelets and tumor cells and its impact on tumor cell behavior and tumor process are analyzed in this work. Phenotypic, genetic and functional modifications induced by platelets were analyzed both in tumor cell lines and in circulating tumor cells (CTCs). Results: Data from these assays showed that platelets transferred structural components to tumor cells with higher efficiency than tumor cells to platelets (p = 0.001). This biological interplay occurred by direct contact, internalization or via extracellular vesicles. As a result, tumor cells acquired platelet markers (CD61 and CD42), showed decreased EpCAM, expressed epithelial-to-mesenchymal transition markers, and increased proliferation rates. Moreover, we were able to detect CD61 in CTCs from early and advanced prostate cancer. Conclusions: Our results demonstrated, for the first time, that platelets educate tumor cells by highly efficient transference of lipids, proteins and RNA through different mechanisms. These results suggest that tumor cells and CTCs might acquire highly dynamic and aggressive phenotypes due to platelets interaction including EMT, stem-like phenotype and high proliferative rates