# Novel Drug Combinations in Lung Cancer: New Potential Synergies Between 5-FU and Repurposed Drugs
###### Abstract
For instance, combinations of 5-FU with other agents such as leucovorin, oxaliplatin, and irinotecan have been shown to significantly improve outcomes in colorectal cancer patients [35]. Similarly, the combination of 5-FU with newer targeted therapies and natural compounds, like Resveratrol, has shown promise in preclinical studies, suggesting that these combinations can enhance anticancer activity while potentially reducing toxicity [36]. These findings support the ongoing exploration of novel drug combinations to optimize cancer therapy, particularly in challenging malignancies like lung cancer. Given the persistent challenges in treating lung cancer, especially the emergence of drug resistance and significant side effects linked to standard treatments, the selection of these drugs is based on their potential to target key pathways involved in tumor survival and proliferation. Sildenafil, for instance, has been shown to improve drug delivery by enhancing tumor perfusion, while Levosimendan's effects on cellular signaling pathways may inhibit cancer cell proliferation. Resveratrol's ability to modulate apoptotic pathways further supports its use as an adjuvant therapy. This multi-targeted approach could offer a promising strategy for overcoming the limitations of current lung cancer treatments. Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, is traditionally used to treat erectile dysfunction, but has also demonstrated potential in improving the delivery and efficacy of chemotherapeutic agents by modulating blood flow and vascular permeability in tumors [37; 38]. Tezosentan, an endothelin (ET) receptor antagonist, exhibits anticancer properties by targeting ET receptors, which are crucial in processes such as cell proliferation, survival, neovascularization, immune response, and drug resistance [39]. Levosimendan, mainly employed in the management of heart failure due to its calcium sensitizing and vasodilatory properties, has shown promising anticancer potential through drug repurposing. Its effects include inhibition of cancer cell migration, enhancement of hypoxic cell sensitivity to radiation, and organ protection via mitochondrial potassium channels [40]. Levosimendan has demonstrated synergistic effects when used in combination with traditional anticancer drugs like 5-FU, particularly in bladder cancer cells [41]. Finally, Reservoir, a natural polyphenol present in grapes and berries, is renowned for its wide range of anticancer activities, including the suppression of cell proliferation [42], induction of apoptosis [43], and modulation of various signaling pathways involved in tumor growth and metastasis [44; 45]. The selection of these compounds was based on their potential to complement the action of 5-FU through different mechanisms, with the hypothesis that they might enhance its cytotoxic effects while allowing for a reduction in the required dosage and associated side effects. Although this synergy is yet to be confirmed, targeting multiple pathways simultaneously utilizing these combinations shows potential for overcoming drug resistance and possibly enhancing therapeutic outcomes in lung cancer treatment. This research holds significant social and scientific relevance, as lung cancer continues to be one of the top causes of cancer-related deaths globally. The results of this study could aid in the creation of novel therapeutic strategies aimed at improving patient outcomes by providing more effective and targeted treatments for lung cancer. Investigating these drug combinations not only aims to boost the effectiveness of current therapies, but also tackles the persistent issue of drug resistance in cancer treatment, which poses a significant obstacle to successful long-term disease management.