The discovery of bioactive compounds for non-invasive therapy has been the goal of research groups focused on pharmacotherapy. Phytonutrients have always been attractive for researchers because they are a significant source of bioactive phytochemicals. Still, it is challenging to determine which components show high biomedical activity and bioavailability after administration. However, based on the chemical structure of these phytochemicals, their physicochemical properties can be calculated to predict the probability of gastrointestinal (GI) absorption after oral administration. Indeed, different researchers have proposed several rules (e.g., Lipinski’s, Veber’s, Ghose’s, and Muegge’s rules) to attain these predictions, but only for synthetic compounds. Most phytochemicals do not fully comply with these rules even though they show high bioactivity and high GI absorption experimentally. Here, we propose a detailed methodology using scientifically validated web-based platforms to determine the physicochemical properties of five phytochemicals found in ginger, echinacea, and tobacco. Furthermore, we analyzed the calculated data and established a protocol based on the integration of these classical rules, plus other extended parameters, that we called the Phytochemical Rule, to obtain a more reliable prediction of the GI absorption of natural compounds. This methodology can help evaluate bioactive phytochemicals as potential drug candidates and predict their oral bioavailability in patients.

Phytonutrients are plant foods that contain many natural bioactive compounds, called phytochemicals, which show specific biological activities. These phytonutrients and their phytochemicals may play an important role in health care maintaining normal organism functions (as preventives) and fighting against diseases (as therapeutics). Phytonutrients’ components are the primary metabolites (i.e., proteins, carbohydrates, and lipids) and phytochemicals or secondary metabolites (i.e., phenolics, alkaloids, organosulfides, and terpenes). For years, several phytonutrients and their phytochemicals have demonstrated specific pharmacological and therapeutic effects in human health such as anticancer, antioxidant, antiviral, anti-inflammatory, antibacterial, antifungal, and immune response. This review summarizes the effects of the most studied or the most popular phytonutrients (i.e., turmeric, garlic, cinnamon, graviola, and oregano) and any reported contraindications. This article also presents the calculated physicochemical properties of the main phytochemicals in the selected phytonutrients using Lipinski’s, Veber’s, and Ghose’s rules. Based on our revisions for this article, all these phytonutrients have consistently shown great potential as preventives and therapeutics on many diseases in vitro, in vivo, and clinical studies.

Recently, there has been great interest in plant-derived compounds known as phytochemicals. The pentacyclic oleanane-, ursane-, and lupane-type triterpenes are phytochemicals that exert significant activity against diseases like cancer. Lung cancer is the leading cause of cancer-related death worldwide. Although chemotherapy is the treatment of choice for lung cancer, its effectiveness is hampered by the dose-limiting toxic effects and chemoresistance. Herein, we investigated six pentacyclic triterpenes, oleanolic acid, ursolic acid, asiatic acid, betulinic acid, betulin, and lupeol, on NSCLC A549 cells. These triterpenes have several structural variations that can influence the activation/inactivation of key cellular pathways. From our results, we determined that most of these triterpenes induced apoptosis, S-phase and G2/M-phase cycle arrest, the downregulation of ribonucleotide reductase (RR), reactive oxygen species, and caspase 3 activation. For chemoresistance markers, we found that most triterpenes downregulated the expression of MAPK/PI3K, STAT3, and PDL1. In contrast, UrA and AsA also induced DNA damage and autophagy. Then, we theoretically determined other possible molecular targets of these triterpenes using the online database ChEMBL. The results showed that even slight structural changes in these triterpenes can influence the cellular response. This study opens up promising perspectives for further research on the pharmaceutical role of phytochemical triterpenoids.

Nanosized drug delivery systems (DDS) have been studied as a novel strategy against cancer due to their potential to simultaneously decrease drug inactivation and systemic toxicity and increase passive and/or active drug accumulation within the tumor(s). Triterpenes are plant-derived compounds with interesting therapeutic properties. Betulinic acid (BeA) is a pentacyclic triterpene that has great cytotoxic activity against different cancer types. Herein, we developed a nanosized protein-based DDS of bovine serum albumin (BSA) as the drug carrier combining two compounds, doxorubicin (Dox) and the triterpene BeA, using an oil-water-like micro-emulsion method. We used spectrophotometric assays to determine protein and drug concentrations in the DDS. The biophysical properties of these DDS were characterized using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy, confirming nanoparticle (NP) formation and drug loading into the protein structure, respectively. The encapsulation efficiency was 77% for Dox and 18% for BeA. More than 50% of both drugs were released within 24 h at pH 6.8, while less drug was released at pH 7.4 in this period. Co-incubation viability assays of Dox and BeA alone for 24 h demonstrated synergistic cytotoxic activity in the low μM range against non-small-cell lung carcinoma (NSCLC) A549 cells. Viability assays of the BSA-(Dox+BeA) DDS demonstrated a higher synergistic cytotoxic activity than the two drugs with no carrier. Moreover, confocal microscopy analysis confirmed the cellular internalization of the DDS and the accumulation of the Dox in the nucleus. We determined the mechanism of action of the BSA-(Dox+BeA) DDS, confirming S-phase cell cycle arrest, DNA damage, caspase cascade activation, and downregulation of epidermal growth factor receptor (EGFR) expression. This DDS has the potential to synergistically maximize the therapeutic effect of Dox and diminish chemoresistance induced by EGFR expression using a natural triterpene against NSCLC.

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal’s body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action’s molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.

The discovery of more bioactive compounds for non-invasive administration has been the goal of research groups focused on pharmacotherapy. Phytonutrients have always been attractive for researchers because they are a significant source of bioactive phytochemicals, but it is challenging to determine which components show high biomedical activity. However, based on the chemical structure of these active compounds, their physicochemical properties can be calculated to predict the probability of gastrointestinal (GI) absorption after oral administration. Indeed, different researchers have proposed several rules (e.g., Lipinski's, Veber's, Ghose's, and Muegge's rules) to attain these predictions for synthetic compounds. Most phytochemicals do not fully comply with these rules even though they show high bioactivity and high GI absorption experimentally. Here, we provide a detailed methodology using web-based platforms to determine the physicochemical properties of five phytochemicals in the phytonutrients ginger, echinacea, and tobacco. Furthermore, we analyzed the calculated data and established a protocol based on the combination and integration of these rules, plus other extended parameter ranges, to reliably predict the GI absorption of natural compounds. The presented data and methodology can be beneficial for evaluating bioactive natural compounds as potential drug candidates and predicting their oral bioavailability in patients.