Advances in Quercetin for Drug-Resistant Cancer Therapy: Mechanisms, Applications, and Delivery Systems.

Quercetin (QUE), a natural flavone abundantly discovered in fruits, has gained attention for its potential health benefits due to its unique structure. In addition, epidemiological and clinical studies have shown promising antioxidant activity of QUE aiming to treat various diseases, including cancer. This article's purpose is to provide an overview of recent advances in the use of QUE for drug-resistant cancer therapies, focusing on its mechanisms, applications, and delivery systems. The review discusses the structure-function relationship of QUE and its role in mitigating various disorders. Furthermore, it highlights the impact of QUE on cancer and cancer stem cells, elucidating the signaling pathways at the cellular and molecular levels involved. Additionally, the review explores the mechanistic role of QUE in reversing drug resistance in different types of drug-resistant cancers. Moreover, it presents a comprehensive analysis of drug diverse delivery strategies employed for effective cancer treatment using QUE. Clinical studies investigating the safety and bioavailability of QUE are also discussed. Finally, the review concludes with future directions, emphasizing the use of cost-effective and efficient protein and peptide-based self-assembling hydrogels for targeted delivery of QUE.

Unleashing the Power of Yes-Associated Protein in Ferroptosis and Drug Resistance in Breast Cancer, with a Special Focus on Therapeutic Strategies.

The YAP protein is a critical oncogenic mediator within the Hippo signaling pathway and has been implicated in various cancer types. In breast cancer, it frequently becomes activated, thereby contributing to developing drug-resistance mechanisms. Recent studies have underscored the intricate interplay between YAP and ferroptosis within the breast tumor microenvironment. YAP exerts a negative regulatory effect on ferroptosis, promoting cancer cell survival and drug resistance. This review offers a concise summary of the current understanding surrounding the interplay between the YAP pathway, ferroptosis, and drug-resistance mechanisms in both bulk tumor cells and cancer stem cells. We also explore the potential of natural compounds alone or in combination with anticancer therapies for targeting the YAP pathway in treating drug-resistant breast cancer. This approach holds the promise of enhancing the effectiveness of current treatments and paving the way for developing novel therapeutics.

Insight into drug sensitizing effect of diallyl disulfide and diallyl trisulfide from Allium sativum L. on paclitaxel-resistant triple-negative breast cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Ayurvedic practitioners and herbal healers in India and China have extensively used garlic (Allium sativum L.) to treat cancers. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are major volatile organosulfur phytochemical constituents found in garlic. AIM OF THE STUDY: To find new insight into the drug sensitizing effect of DADS and DATS on paclitaxel (PTX)-resistant triple-negative breast cancer cells (TNBC/PR). MATERIALS AND METHODS: This study estimates the non-toxic concentration of DADS and DATS against normal healthy breast epithelial cell line (MCF-12A) by using a trypan blue viability assay. Also, it evaluates the effect of DADS and DATS on the sensitization of established stable TNBC/PR cell clones (MDA-MB 231 PR and MDA-MB 468 PR) by MTT, BrdU incorporation, intracellular ROS, cell cycle, and apoptosis assays. RESULTS: The results show that DADS and DATS are non-cytotoxicity against MCF-12A cells. Nevertheless, DADS and DATS have shown significantly high cytotoxicity against MDA-MB 231 PR and MDA-MB 468 PR cells. They also inhibited PTX-resistant cell proliferation by blocking the cell cycle. Further, they induced apoptosis by activation of caspase 3 and 9. N-acetyl cysteine pre-treatment inhibited DADS and DATS-induced intracellular ROS release. In silico study shows that DADS and DATS interact with a large extracellular loop (LEL) of CD151 with a binding energy of -4.0 kcal/mol and transmembrane domain (TM) with a binding affinity of 11.7 and 13.6 kcal/mol, respectively. They also inhibited the surface expression of CD151 in TNBC/PR cells. CONCLUSION: This study implies that DADS and DATS could be considered for sensitizing drug-resistant breast cancers.

Tumor-associated macrophages: Potential target of natural compounds for management of breast cancer.

A large body of experimental research reveals that tumor-associated macrophages (TAMs) are the major immunosuppressor cells in the breast tumor microenvironment (TME). The infiltration of macrophages is correlated with inverse outcomes like disease-free survival and overall survival of cancer patients. They are responsible for heterogeneity, metastasis, and drug resistance. Further, their density in tumor beds is correlated with stage and therapy response. The current review is aimed at summarizing mechanisms and signaling pathways that modulate immune-suppressive phenotype and expansion of TAMs. The review presents an overview of the interdependence of tumor cells and TAMs in TME to promote metastasis, drug resistance and immune suppressive phenotype. This review also presents the potential natural compounds that modulate the immune-suppressive functions of TAMs and their signaling pathways. Finally, this review provides nanotechnology approaches for the targeted delivery of natural products. This review shed light on BC management including clinical studies on the prognostic relevance of TAMs and natural compounds that sensitizes BC.