# Novel Drug Combinations in Lung Cancer: New Potential Synergies Between 5-FU and Repurposed Drugs
## 4 Discussion
These mechanisms, coupled with Levosimendan's favorable safety profile observed in non-cancerous cells, underscore its potential as a therapeutic adjunct to 5-FU and other standard treatments. Resveratrol, on the other hand, exhibits potent anticancer effects through the downregulation of nuclear factor kappa B (NF-kB), a key transcription factor involved in promoting inflammation, cell proliferation, and survival [44]. The inhibition of NF-kB signaling by Resveratrol leads to enhanced apoptosis and decreased tumor cell proliferation. Furthermore, Resveratrol interferes with the PI3K/Akt and mTOR pathways, both of which are often implicated in chemotherapy resistance [45; 61; 62]. By disrupting these pathways, Resveratrol not only sensitizes cancer cells to chemotherapeutic agents like 5-FU, but also limits their long-term survival and ability to evade treatment. Similar morphological changes in lung cancer have been documented in other studies where Resveratrol induced apoptosis and cell-cycle arrest, further validating our observations [63; 64]. In previous studies, Resveratrol has shown consistent anticancer activity in several cancer models. In renal cell carcinoma [65] and pancreatic cancer cells [66], Resveratrol was effective in reducing clonogenic potential through pathways involving Akt and ERK1/2 signaling and FOXO transition factor activation. The observed reduction in cell viability and clonogenicity in A549 cells, particularly when combined with 5-FU,aligns with these broader findings, reinforcing Resveratrol's broad anticancer potential across different cancer types. These results underscore the importance of carefully selecting drug combinations in cancer therapy, where agents like Resveratrol could be prioritized for their ability to enhance the efficacy of standard treatments like 5-FU. The comparable efficacy of the Resveratrol and Levosimendan combination to IC\({}_{50}\) 5-FU in reducing cell viability (by 40% with Levosimendan, \(p<0.01\)) and clonogenic potential suggests that this combination could be a promising alternative, particularly for patients who may not tolerate standard chemotherapy well. These drug combinations could be especially beneficial for patients with advanced-stage lung cancer, those who have developed resistance to conventional treatments, or those unable to tolerate high doses of 5-FU due to severe side effects. By reducing the dosage of 5-FU while maintaining therapeutic efficacy through combination therapies, it is possible to mitigate some of the associated toxicities, offering a safer alternative for certain patient populations. Furthermore, the reduction in clonogenicity observed with these combinations highlights their potential in targeting tumor recurrence, a significant challenge in long-term cancer management. However, several limitations must be acknowledged. First, the drug concentrations used in this in vitro study may not directly correspond to those achievable in vivo. Factors such as drug metabolism, distribution, and clearance in the body could influence the efficacy and safety profiles of these combinations. Additionally, the use of a single lung cancer cell line (A549) may limit the generalizability of our findings to other lung cancer subtypes, such as squamous cell carcinoma or SCLC, which could respond differently to these treatments. Future studies incorporating a wider range of lung cancer cell lines will be essential to determine whether the observed effects are applicable across different subtypes. Furthermore, while the in vitro results are promising, translating these findings into clinical practice presents challenges. Tumor microenvironments in vivo, variability in patient responses, and potential drug interactions could affect the efficacy of these combinations. Before advancing to clinical trials, it is crucial to further investigate the pharmacokinetics, optimal dosing regimens, and potential toxicities of these drug combinations in more complex biological systems.