# Novel Drug Combinations in Lung Cancer: New Potential Synergies Between 5-FU and Repurposed Drugs
###### Abstract  
The therapeutic potential of combining 5-FU with repurposed drugs such as Sildenafil, Tezosentan, Levosimendan, and Resveratrol was investigated in lung cancer treatment using the A549 cell line. This study aimed to enhance 5-FU efficacy while mitigating side effects and overcoming drug resistance. The cytotoxic effects of 5-FU were assessed via MTT assay, with an IC\({}_{50}\) value of 5.03 uM for A549 cells. Subsequent experiments evaluated the impact of combining 5-FU with the aforementioned drugs on cell viability, clonogenic potential, and morphology. The results demonstrated that while Sildenafil and Tezosentan modestly improved 5-FU efficacy, Levosimendan reduced cell viability by 40% (\(p<\) 0.01) and Resveratrol by over 50% (\(p<\) 0.001), with clonogenicity reduced by up to 60% (\(p<\) 0.001). These findings suggest that combining 5-FU with Levosimendan or Resveratrol offers promising approaches for lung cancer therapy, potentially reducing the need for higher doses of 5-FU and minimizing associated toxicity. Future studies are warranted to elucidate the mechanisms underlying these interactions and assess their clinical relevance. A549 cell line; drug combination therapy; lung cancer; 5-FU +
Footnote †: journal: Medical  
cancer typically involve a combination of strategies, including surgery [13], radiation therapy [14], chemotherapy [15], targeted therapy [16], and immunotherapy [17]. In certain cases, hormone therapy may also be considered [18]. The specific treatment plan is tailored to the individual, taking into account factors such as the cancer's stage, tumor location, the patient's overall health, and personalized treatment goals [19]. The compound 5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent utilized in the therapy of multiple cancer types [20]. Since its introduction into clinical practice, 5-FU has been a cornerstone in oncology, playing a critical role in the management of malignant neoplasms, both in adjuvant and palliative chemotherapy regimens [21; 22]. Its effectiveness is largely attributed to its mechanism of action as a pyrimidine analog, where 5-FU disrupts the synthesis of DNA and RNA in tumor cells, leading to the disruption of cell replication and eventually apoptosis [23]. Despite its proven efficacy, the use of 5-FU is accompanied by several limitations. Drug resistance, which can occur due to alterations in the drug's metabolic pathway or changes in the expression of genes related to the cell cycle, is one of the major challenges in cancer treatment with this agent [24; 25]. Furthermore, the adverse side effects, such as myelosuppression [26], gastrointestinal toxicity [27; 28; 29], and cardiotoxicity [30], limit its application, particularly in patients with comorbidities or clinical frailty. These challenges underscore the need for therapeutic strategies that can enhance the efficacy of 5-FU while minimizing its adverse effects, such as combining it with other therapeutic agents that could overcome drug resistance or mitigate its toxic effects. In recent years, the strategy of combining chemotherapeutic agents has gained significant traction as a means to enhance the effectiveness of cancer treatment [31; 32]. The rationale behind drug combination therapy lies in the ability to target multiple pathways simultaneously, thereby enhancing the cytotoxic effects on cancer cells while minimizing the chances of developing drug resistance [33]. By using lower doses of each drug in combination, it is often possible to achieve a synergistic effect, where the combined effect exceeds the total of the individual impacts [34]. This approach not only increases therapeutic efficacy, but also helps to minimize the adverse side effects typically associated with higher doses of single-agent chemotherapy. Numerous studies have shown the advantages of synergistic combinations of drugs in cancer therapy.