👤 Deng LW

Colorectal cancer (CRC) remains a significant global health challenge, ranking third in incidence and second in mortality among cancers worldwide. This review addresses the complex landscape of CRC, focusing on incidence, mortality trends, preventive strategies, and the evolving therapeutic approaches, particularly highlighting the role of platinum-based drugs like oxaliplatin (OXP). It also underscores the increasing burden of CRC, with factors such as westernized diets, aging populations, and genetic predispositions contributing to its prevalence. Therapeutically, early detection greatly enhances survival rates, emphasizing the importance of regular colonoscopies and stool tests. For advanced CRC, chemotherapy remains pivotal, with OXP as a cornerstone treatment despite its associated chemotherapy-induced peripheral neurotoxicity (CIPN). The review explores innovative strategies to overcome challenges related to chemotherapy, such as drug resistance and side effects, highlighting recent developments in the field, such as Pt(IV) prodrugs and immunotherapeutic approaches to enhance efficacy while minimizing toxicity. Additionally, this manuscript examines experimental models for drug screening, emphasizing the role of murine models and advanced 3D in vitro systems in CRC research. Overall, the review advocates for a comprehensive approach, integrating prevention, early detection, and personalized treatments to alleviate the global burden of CRC. Show less

Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new synergistic combinations for PARPi, we screened a "micro-library" comprising a mix of commercially available drugs and DNA-binding ruthenium(II) polypyridyl complexes (RPCs) for Olaparib synergy in BRCA-proficient triple-negative breast cancer cells. This identified three hits: the natural product Curcumin and two ruthenium(II)-rhenium(I) polypyridyl metallomacrocycles. All combinations identified were effective in BRCA-proficient breast cancer cells, including an Olaparib-resistant cell line, and spheroid models. Mechanistic studies indicated that synergy was achieved via DNA-damage enhancement and resultant apoptosis. Combinations showed low cytotoxicity toward non-malignant breast epithelial cells and low acute and developmental toxicity in zebrafish embryos. This work identifies RPC metallomacrocycles as a novel class of agents for cancer combination therapy and provides a proof of concept for the inclusion of metallocompounds within drug synergy screens. Show less