Exploring Natural Compounds Targeting PD-L1 and STAT3: Toxicogenomic Analysis, Virtual Screening, Molecular Docking, ADMET Evaluation, and Biological Activity Prediction.

BACKGROUND: One of the most important targets in cancer immunotherapy is programmed cell death ligand 1 (PD-L1). Monoclonal antibodies developed for this target have disadvantages due to their low bioavailability and some immune-related adverse effects. Additionally, small molecules targeting PD-L1 are still in the experimental stage. At this point, discovering non-toxic natural compounds that directly or indirectly target PD-L1 is essential. In this in silico study, a comprehensive literature search was conducted to identify publications reporting the master regulator of PD-L1, which was suggested as a Signal Transducer and Activator of Transcription 3 (STAT3). The relationship between STAT3 and PD-L1 was further investigated through bioinformatic analysis. METHOD: Subsequently, natural compounds targeting PD-L1 and STAT3 were screened, and compounds with suitable toxicity profiles were docked against both PD-L1 and STAT3. Following molecular docking, the selected molecules underwent DNA docking, ADMET profile analysis, and in silico assessment of biological activities. The relationship between PD-L1 and STAT3 was determined in 52 out of the 453 articles, and it was further demonstrated in genegene interactions. Following the virtual screening, 76 natural compounds were identified, and after pre-filtering based on physicochemical properties, drug-likeness, and ADMET profiles, 29 compounds remained. RESULT: Subsequent docking revealed that two compounds, 6-Prenylapigenin, and Gelomulide J, persisted. ADMET and biological activity prediction results suggested that 6-Prenylapigenin is non-toxic and has the potential to inhibit PD-L1 and STAT3 in silico. The present study highlights that STAT3 serves as the master regulator of PD-L1, and it further suggests that 6- Prenylapigenin exhibits the potential to modulate PD-L1 and/or STAT3. CONCLUSION: This finding could pave the way for the development of small molecules designed to block the PD-1/PD-L1 interaction by silencing the PD-L1 and/or STAT3 genes or reducing protein levels.

Assessment of redox homeostasis via genotoxicity, cytotoxicity, apoptosis and NRF-2 in colorectal cancer cell lines after treatment with Ganoderma lucidum extract.

This study aimed to investigate the cytotoxic and apoptotic effects of Ganoderma lucidum, Pleurotus ostreatus, Pleurotus eryngii, and Inonotus hispidus fungal extracts on HT-29 and HCT-116 colorectal cancer cell lines and to search the DNA damage and oxidative stress caused by these extracts. Accordingly, mushroom extracts were applied to colorectal cancer cell lines in vitro, and the IC50 result was obtained with the MTT test. According to the IC50 result, Ganoderma lucidum extract had the most effective cytotoxicity value among all used mushroom extracts. TAS, TOS, and NRF-2 tests were used to investigate the molecular effect of Ganoderma lucidum extract on oxidative stress; the DNA ladder test was performed to assess DNA damage, the Scratch assay method was applied for cell migration analysis, and the colony assay was used to determine the colony formation potential of the cells. The results showed that Ganoderma lucidum mushroom extract reduces cell proliferation, colony formation, and NRF-2, induces DNA damage, slows cell migration, and increases oxidative stress. This study shows that Ganoderma lucidum mushroom extract reduces cell proliferation through damaging cellular DNA and has a cytotoxic effect in colorectal cancer cell lines.