Molecular insights to therapeutic in cancer: role of exosomes in tumor microenvironment, metastatic progression and drug resistance.

Exosomes play a pivotal part in cancer progression and metastasis by transferring various biomolecules. Recent research highlights their involvement in tumor microenvironment remodeling, mediating metastasis, tumor heterogeneity and drug resistance. The unique cargo carried by exosomes garners the interest of researchers owing to its potential as a stage-specific biomarker for early cancer detection and its role in monitoring personalized treatment. However, unanswered questions hinder a comprehensive understanding of exosomes and their cargo in this context. This review discusses recent advancements and proposes novel ideas for exploring exosomes in cancer progression, aiming to deepen our understanding and improve treatment approaches.

Evodiamine potentiates cisplatin-induced cell death and overcomes cisplatin resistance in non-small-cell lung cancer by targeting SOX9-ß-catenin axis.

BACKGROUND: In recent decades, phytotherapy has remained as a key therapeutic option for the treatment of various cancers. Evodiamine, an excellent phytocompound from Evodia fructus, exerts anticancer activity in several cancers by modulating drug resistance. However, the role of evodiamine in cisplatin-resistant NSCLC cells is not clear till now. Therefore, we have used evodiamine as a chemosensitizer to overcome cisplatin resistance in NSCLC. METHODS: Here, we looked into SOX9 expression and how it affects the cisplatin sensitivity of cisplatin-resistant NSCLC cells. MTT and clonogenic assays were performed to check the cell proliferation. AO/EtBr and DAPI staining, ROS measurement assay, transfection, Western blot analysis, RT-PCR, Scratch & invasion, and comet assay were done to check the role of evodiamine in cisplatin-resistant NSCLC cells. RESULTS: SOX9 levels were observed to be higher in cisplatin-resistant A549 (A549CR) and NCI-H522 (NCI-H522CR) compared to parental A549 and NCI-H522. It was found that SOX9 promotes cisplatin resistance by regulating ß-catenin. Depletion of SOX9 restores cisplatin sensitivity by decreasing cell proliferation and cell migration and inducing apoptosis in A549CR and NCI-H522CR. After evodiamine treatment, it was revealed that evodiamine increases cisplatin-induced cytotoxicity in A549CR and NCI-H522CR cells through increasing intracellular ROS generation. The combination of both drugs also significantly inhibited cell migration by inhibiting epithelial to mesenchymal transition (EMT). Mechanistic investigation revealed that evodiamine resensitizes cisplatin-resistant cells toward cisplatin by decreasing the expression of SOX9 and ß-catenin. CONCLUSION: The combination of evodiamine and cisplatin may be a novel strategy for combating cisplatin resistance in NSCLC.

Enigmatic exosomal connection in lung cancer drug resistance.

Lung cancer remains a significant global health concern with limited treatment options and poor prognosis, particularly in advanced stages. Small extracellular vesicles such as exosomes, secreted by cancer cells, play a pivotal role in mediating drug resistance in lung cancer. Exosomes have been found to facilitate intercellular communication by transferring various biomolecules between cancer cells and their microenvironment. Additionally, exosomes can transport signaling molecules promoting cancer cell survival and proliferation conferring resistance to chemotherapy. Moreover, exosomes can modulate the tumor microenvironment by inducing phenotypic changes hindering drug response. Understanding the role of exosomes in mediating drug resistance in lung cancer is crucial for developing novel therapeutic strategies and biomarkers to overcome treatment limitations. In this review, we summarize the current knowledge on conventional and emerging drug resistance mechanisms and the involvement of exosomes as well as exosome-mediated factors mediating drug resistance in lung cancer.

Transforming native exosomes to engineered drug vehicles: A smart solution to modern cancer theranostics.

Exosomes have been the hidden treasure of the cell in terms of cellular interactions, transportation and therapy. The native exosomes (NEx) secreted by the parent cells hold promising aspects in cancer diagnosis and therapy. NEx has low immunogenicity, high biocompatibility, low toxicity and high stability which enables them to be an ideal prognostic biomarker in cancer diagnosis. However, due to heterogeneity, NEx lacks specificity and accuracy to be used as therapeutic drug delivery vehicle in cancer therapy. Transforming these NEx with their innate structure and multiple receptors to engineered exosomes (EEx) can provide better opportunities in the field of cancer theranostics. The surface of the NEx exhibits numeric receptors which can be modified to pave the direction of its therapeutic drug delivery in cancer therapy. Through surface membrane, EEx can be modified with increased drug loading potentiality and higher target specificity to act as a therapeutic nanocarrier for drug delivery. This review provides insights into promising aspects of NEx as a prognostic biomarker and drug delivery tool along with its need for the transformation to EEx in cancer theranostics. We have also highlighted different methods associated with NEx transformations, their nano-bio interaction with recipient cells and major challenges of EEx for clinical application in cancer theranostics.

Tumour microenvironment and aberrant signaling pathways in cisplatin resistance and strategies to overcome in oral cancer.

OBJECTIVE: Oral cancer is the sixteenth most prevalent cancer in the world and the third-most in India. Despite of several treatment modalities, the cure rate of oral cancer is still low due to drug resistance mechanisms, which are caused by many reasons. It is necessary to improve the existing treatment strategies and discover neoteric therapy to kill cancer cells, which will give oral cancer's cure rate more success. So this review aims to delineate the molecular mechanisms behind cisplatin resistance, specifically the role of the tumor microenvironment, extracellular vesicles, and altered signaling pathways and its overcoming strategies in oral cancer. DESIGN: This review was designed by searching words like cancer, oral cancer, cisplatin-resistance, tumor microenvironment, aberrant signalings, and extracellular vesicles, overcoming strategies for cisplatin resistance in databases like PubMed, Google Scholar, web science, and Scopus. Data available in this review is from 2017 to 2021. RESULTS: After searching too much data, we found these 98 data appropriate for our review. From these data, we found that tumor microenvironment, extracellular vesicles, and altered signaling pathways like PI3K/AKT, EGFR, NOTCH, Ras, PTEN, Nf-κß, and Wnt signaling have a crucial role in resistance development towards cisplatin in oral cancer. CONCLUSIONS: Lastly, this review explores the alternative strategies to overcome cisplatin resistance likely, the combination therapy and targeted therapy by combining more than one chemotherapeutic drug or inhibitors of signaling pathways and also by using nanoparticle loaded drugs that will reduce the drug efflux, which gives new treatment strategies.