MOLECULAR INSIGHTS INTO PHYTOCHEMICAL-PROTEIN INTERACTIONS: A PARADIGM SHIFT IN BREAST CANCER THERAPY

Abstract

Muhammad Akram Shahzad Khokhar, Malik Ihsan Ullah Khan, Arif Malik, Gul Zaib, Haleema Saadia, Qurban Ali

Breast cancer is among the most common cancers, and for cancer treatment, it calls for fresh strategies. Flavonoids as phytochemicals are natural bioactive compounds showing luminous prospects as anti-cancer given their specific action against proteins. The current work focuses on the impact of phytochemicals on proteins related to breast cancer as a new approach to therapy. The study looks at the performance of phytochemicals including CBD (Cannabidiol), THC (Tetrahydrocannabinol), and EGCG (Epigallocatechin-3-Gallate) concerning conventional chemotherapy drugs including paclitaxel and zoledronic acid. AutoDock Vina was used to predict the binding energy of phytochemicals and standard drugs to the target proteins in BCa progression, including HER2 (Human Epidermal Growth Factor Receptor 2), ER (Endoplasmic Reticulum), VEGF (Vascular Endothelial Growth Factor), etc. Pharmacokinetic profiling was performed using ADMET prediction and toxicity screening was done using ProTox-II. Further, using ELISA (Enzyme-Linked Immunosorbent Assay) assays, the present study examined the alterations in the serum protein levels using phytochemicals versus standard drug in CA breast rat model. Data analysis was based on the level of statistical significance which was set at p ≤ 0.05*. EGCG binds most strongly to VEGF (Vascular Endothelial Growth Factor) (-10.5 kcal/mol) and PR (Peregrine Falcon) (-9.7 kcal/mol) among all the flavonols investigated. THC had a better docking score for EGFR (-10.6 kcal/mol) while CBD had a better docking score with ER (-9.8 kcal/mol) and PD-L1 (-9.8 kcal/mol). By the ADME (Absorption, Distribution, Metabolism, And Excretion) analysis, the intestinal absorption, permeability, and oral bioavailability of phytochemicals showed moderate to a high level of 20%-60% consequently, the level of hepatotoxicity and mutagenic potential had a low level. Quantification of serum proteins also revealed reduced HER2 levels in the EGCG group (2.12 ng/mL ± 0.39 ng/mL) than in the control group (3.21 ng/mL ± 0.47 ng/mL. EGCG also increases the level of ER (5.22 ± 0.74 ng/mL, p=0.011) and decreases Ki-67 (1.22 ng/mL ± 0.23 ng/mL, p=0.02). Phytochemicals were evaluated by toxicity analysis to be safer than the chemotherapeutic drugs commonly used to treat different types of cancer. The study sheds light upon the effects of phytochemicals such as EGCG, and cannabinoids like CBD (Cannabidiol) and THC (Tetrahydrocannabinol) in regulating BC related proteins. These compounds have been considered highly effective and safe compared to traditional medicines making the management of breast cancer quite different. Further in vivo and clinical investigations are needed to confirm these results and enable the future translation of the approach.