Chemotherapeutic potential of lupeol against cancer in pre-clinical model: A systematic review and meta-analysis.

BACKGROUND: Extensive research on Lupeol's potential in cancer prevention highlights its ability to target various cancer-related factors. It regulates proliferative markers, modulates signaling pathways, including PI3K/AKT/mTOR, and influences inflammatory and apoptotic mechanisms. Additionally, Lupeol demonstrates selectivity in killing cancer cells while sparing normal cells, thus minimizing the risk of toxic effects on healthy tissues. HYPOTHESIS: Therefore, we aimed to explore Lupeol's potential roles as a chemotherapeutic agent and as a sensitizer to chemotherapy by reviewing various animal-based studies published on its effects. STUDY DESIGN: We conducted a comprehensive search across databases, including PubMed, PMC, Cochrane, EuroPMC, and ctri.gov.in to identify pertinent articles. Our focus was solely on published animal studies examining Lupeol's anti-cancer effects, with reviewers independently assessing bias risk and resolving discrepancies through consensus. RESULT: 20 studies were shortlisted. The results demonstrated that Lupeol brings changes in the tumor volume by [Hedges's g: -6.62; 95 % CI: -8.68, -4.56; τ2: 24.36, I2: 96.50 %; p < 0.05] and tumor weight by [Hedges's g: -3.97; 95 % CI: -5.20, -2.49; τ2: 2.70, I2: 79.27 %; p <0.05]. The high I2, negative Egger's value, and asymmetrical funnel plot show the publication bias among the studies. Further, Lupeol in combination with other chemotherapeutic agents showed better outcomes as compared to them alone [Hedges's g: -6.38; 95 % CI: -11.82, -0.94; τ2: 46.91; I2: 98.68 %; p <0.05]. Lupeol also targets various signaling molecules and pathways to exert an anti-cancer effect. CONCLUSION: In conclusion, Lupeol significantly reduces tumor volume and weight. Combining Lupeol with other chemotherapy agents shows promise for enhancing anti-cancer effects. However, high variability among studies and evidence of publication bias suggest caution in interpreting results.

Apigenin enhances sorafenib anti-tumour efficacy in hepatocellular carcinoma.

BACKGROUND: The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore. METHODS: We used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 µM) and Sorafenib (1-10 µM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done. RESULTS: The results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4. CONCLUSIONS: In conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.

Cancer cell plasticity, stem cell factors, and therapy resistance: how are they linked?

Cellular plasticity can occur naturally in an organism and is considered an adapting mechanism during the developmental stage. However, abnormal cellular plasticity is observed in different diseased conditions, including cancer. Cancer cell plasticity triggers the stimuli of epithelial-mesenchymal transition (EMT), abnormal epigenetic changes, expression of stem cell factors and implicated signaling pathways, etc., and helps in the maintenance of CSC phenotype. Conversely, CSC maintains the cancer cell plasticity, EMT, and epigenetic plasticity. EMT contributes to increased cell migration and greater diversity within tumors, while epigenetic changes, stem cell factors (OCT4, NANOG, and SOX2), and various signaling pathways allow cancer cells to maintain various phenotypes, giving rise to intra- and inter-tumoral heterogeneity. The intricate relationships between cancer cell plasticity and stem cell factors help the tumor cells adopt drug-tolerant states, evade senescence, and successfully acquire drug resistance with treatment dismissal. Inhibiting molecules/signaling pathways involved in promoting CSCs, cellular plasticity, EMT, and epigenetic plasticity might be helpful for successful cancer therapy management. This review discussed the role of cellular plasticity, EMT, and stem cell factors in tumor initiation, progression, reprogramming, and therapy resistance. Finally, we discussed how the intervention in this axis will help better manage cancers and improve patient survivability.

Epithelial-to-mesenchymal transition in cancer progression: unraveling the immunosuppressive module driving therapy resistance.

Cancer cells undergo phenotypic switching (cancer cell plasticity) in response to microenvironmental cues, including exposure to therapy/treatment. Phenotypic plasticity enables the cancer cells to acquire more mesenchymal traits promoting cancer cells' growth, survival, therapy resistance, and disease recurrence. A significant program in cancer cell plasticity is epithelial-to-mesenchymal transition (EMT), wherein a comprehensive reprogramming of gene expression occurs to facilitate the translational shift from epithelial-to-mesenchymal phenotypes resulting in increased invasiveness and metastasis. In addition, EMT plays a pivotal role in facilitating cancer cells' escape from the body's immune system using several mechanisms, such as the downregulation of major histocompatibility complex-mediated antigen presentation, upregulation of immune checkpoint molecules, and recruitment of immune-suppressive cells. Cancer cells' ability to undergo phenotypic switching and EMT-driven immune escape presents a formidable obstacle in cancer management, highlighting the need to unravel the intricate mechanisms underlying these processes and develop novel therapeutic strategies. This article discusses the role of EMT in promoting immune evasion and therapy resistance. We also discuss the ongoing research on developing therapeutic approaches targeting intrinsic and induced cell plasticity within the immune suppressive microenvironment. We believe this review article will update the current research status and equip researchers, clinicians, and other healthcare professionals with valuable insights enhancing their existing knowledge and shedding light on promising directions for future cancer research. This will facilitate the development of innovative strategies for managing therapy-resistant cancers and improving patient outcomes.

Unveiling the therapeutic promise of natural products in alleviating drug-induced liver injury: Present advancements and future prospects.

Drug-induced liver injury (DILI) refers to adverse reactions to small chemical compounds, biological agents, and medical products. These reactions can manifest as acute or chronic damage to the liver. From 1997 to 2016, eight drugs, including troglitazone, nefazodone, and lumiracoxib, were removed from the market due to their liver-damaging effects, which can cause diseases. We aimed to review the recent research on natural products and their bioactive components as hepatoprotective agents in mitigating DILI. Recent articles were fetched via searching the PubMed, PMC, Google Scholar, and Web of Science electronic databases from 2010 to January 2023 using relevant keywords such as "natural products," "acetaminophen," "antibiotics," "paracetamol," "DILI," "hepatoprotective," "drug-induced liver injury," "liver failure," and "mitigation." The studies reveal that the antituberculosis drug (acetaminophen) is the most frequent cause of DILI, and natural products have been largely explored in alleviating acetaminophen-induced liver injury. They exert significant hepatoprotective effects by preventing mitochondrial dysfunction and inflammation, inhibiting oxidative/nitrative stress, and macromolecular damage. Due to the bioavailability and dietary nature, using natural products alone or as an adjuvant with existing drugs is promising. To advance DILI management, it is crucial to conduct well-designed randomized clinical trials to evaluate natural products' efficacy and develop new molecules clinically. However, natural products are a promising solution for remedying drug-induced hepatotoxicity and lowering the risk of DILI.

Molecular Insight into Prostate Cancer: Preventive Role of Selective Bioactive Molecules.

Prostate cancer (CaP) is one of the most prevalent male malignancies, accounting for a considerable number of annual mortalities. However, the prompt identification of early-stage CaP often faces delays due to diverse factors, including socioeconomic inequalities. The androgen receptor (AR), in conjunction with various other signaling pathways, exerts a central influence on the genesis, progression, and metastasis of CaP, with androgen deprivation therapy (ADT) serving as the primary therapeutic strategy. Therapeutic modalities encompassing surgery, chemotherapy, hormonal intervention, and radiotherapy have been formulated for addressing early and metastatic CaP. Nonetheless, the heterogeneous tumor microenvironment frequently triggers the activation of signaling pathways, culminating in the emergence of chemoresistance, an aspect to which cancer stem cells (CSCs) notably contribute. Phytochemicals emerge as reservoirs of bioactive agents conferring manifold advantages against human morbidity. Several of these phytochemicals demonstrate potential chemoprotective and chemosensitizing properties against CaP, with selectivity exhibited towards malignant cells while sparing their normal counterparts. In this context, the present review aims to elucidate the intricate molecular underpinnings associated with metastatic CaP development and the acquisition of chemoresistance. Moreover, the contributions of phytochemicals to ameliorating CaP initiation, progression, and chemoresistance are also discussed.

Lupeol, an androgen receptor inhibitor, enhances the chemosensitivity of prostate cancer stem cells to antiandrogen enzalutamide-based therapy.

Enzalutamide is an androgen receptor (AR) antagonist commonly used in the treatment of prostate cancer (CaP). However, due to the potential toxicity and development of resistance associated with Enzalutamide-based therapy, there is a need to explore additional compounds that can enhance its therapeutic effectiveness while minimizing toxicity. Lupeol is a pharmacologically active triterpene having anticancer effects. The objective of this study was to explore Lupeol's potential in enhancing the chemosensitivity of chemoresistant CaP cells to Enzalutamide in vitro and in a mouse model. To test our hypothesis, we performed cell viability and luciferase reporter gene assay, flow cytometry, animal studies, and histopathological analysis. Finally, we analyzed the change in selective metabolites in the prostate tissue by LCMS. Results demonstrated that a combination of Lupeol and Enzalutamide could better (i) suppress the Cancer Stem Cells (CSCs) and chemoresistant cells (PTEN-CaP8 and PC3) viability and migration, (ii) increase cell cycle arrest, (iii) inhibit the transcriptional activity of AR, c-MYC, c-FLIP, and TCF (iv) inhibit tumor growth in a mouse model (v) protect Enzalutamide-induced adverse effects in prostate glands and gut tissue (vi) decrease levels of testosterone and methionine metabolites. In conclusion, Lupeol enhances the pharmacological efficacy of Enzalutamide and reduces the adverse effects. Thus, Lupeol could be a promising adjuvant for improving Enzalutamide-based treatment outcomes and warrant further research.

Role of epigenetic drugs in sensitizing cancers to anticancer therapies: emerging trends and clinical advancements.

Epigenetic changes play a significant role in cancer progression, maintenance and therapy resistance. Generally, epigenetic modifications are reversible, thereby gaining attention for therapeutic interventions. However, limited efficacy and therapy resistance remain the significant limitations of conventional and epigenetic anticancer therapies. Recently, combination therapies with epigenetic drugs (epi-drugs) and conventional anticancer treatment have gained widespread attention. Here, epi-drugs are administered with anticancer therapies to increase their therapeutic efficacy and sensitize cancer cells resistant to therapies. This review summarizes the mechanism of epi-drugs in reversing resistance to anticancer therapies. Further, the challenges faced during developing combination therapies with epi-drugs are discussed. We believe the clinical benefit of combination therapies could be increased by overcoming the challenges faced during epi-drug development.

Epigenetic changes play a significant role in cancer development and progression. Epigenetic drugs (epi-drugs) target enzymes involved in regulating epigenetic changes to maintain normal cell functioning. Epi-drugs include histone deacetylase inhibitors and DNA methyltransferase inhibitors, among others. These drugs have shown potential as standalone treatments for cancer and have also been found to work well in combination with other therapies (chemotherapy, radiotherapy and immunotherapy), helping to overcome treatment resistance. By targeting the epigenetic alterations that contribute to treatment resistance, epi-drugs have the potential to enhance the effectiveness of these therapies. This review article focuses on how epi-drugs overcome resistance to different cancer treatments. Combining epi-drugs with conventional anticancer therapies could provide better management of cancer. However, more preclinical and clinical research is needed to understand the potential benefits and optimize the use of these combinations fully. Overall, epi-drugs offer a promising avenue for improving cancer treatment outcomes and warrant further investigation.

Flubendiamide induced genetic and cellular damages directly influence the life cycle of the oriental leaf worm, Spodoptera litura.

Indiscriminate uses of insecticide greatly damage the environment as well as non-target organisms. Thus, multiple levels of bioassays can help better management of our environment. Flubendiamide is a phthalic acid diamide insecticide that ceases the function of insect muscle leading to paralysis and death. Here, we aimed to explore the effects of Flubendiamide on the life cycle of Spodoptera litura vis-a-vis the mode of action. Fourth instar larvae of the same age (120 ± 2 h) and size were fed with different concentrations (20-80 µg/mL) of Flubendiamide for 12-72 h. We performed a pharmacokinetics study, different biochemical assays, p450, Ecdysone receptor (EcR) and other genes expression analyses by Real-Time PCR and gross damages by Dye exclusion assay and histopathology. Our results demonstrate that the mean concentration of Flubendiamide after 48 h is 9.907 µg/mL and (i) altered the molting, metamorphosis, and reproduction at 80 µg/mL (24 h) (ii) increases all oxidative stress parameters (ROS/RNS, MDA, 8OHdG), decreases oxidative defense mechanisms (SOD, CAT, GST) at 80 µg/mL (48 h) and p450 in a time and concentration-dependent manner, (iii) activates CncC/Maf apoptotic pathways at 80 µg/mL concentration at 24 h while the expression declined from 48 h onwards, (iii) downregulates the EcR expression in a time and concentration-dependent manner, which might be responsible for disturbed molting, metamorphosis, and reproduction, and (iv) increase the expression of apoptotic genes (Caspase 1, -3, and - 5), in time and concentration-dependent manner causing gross morphological and histological damages. In conclusion, indiscriminate use of this insecticide can affect the ecosystem and have the capacity to cause multiple hazardous effects on experimental organisms. Thus, it warrants further investigations to improve and optimize the integrated pest management packages, including Flubendiamide for better management.

Anti-cancer activity of guggulsterone by modulating apoptotic markers: a systematic review and meta-analysis.

Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C21H28O2) is an effective phytosterol isolated from the gum resin of the tree Commiphora wightii (Family Burseraceae) and is responsible for many of the properties of guggul. This plant is widely used as traditional medicine in Ayurveda and Unani system of medicine. It exhibits several pharmacological activities, such as anti-inflammatory, analgesic, antibacterial, anti-septic and anticancer. In this article, the activities of Guggulsterone against cancerous cells were determined and summarized. Methods: Using 7 databases (PubMed, PMC, Google Scholar, Science Direct, Scopus, Cochrane and Ctri.gov), the literature search was conducted since conception until June 2021. Extensive literature search yielded 55,280 studies from all the databases. A total of 40 articles were included in the systematic review and of them, 23 articles were included in the meta-analysis.The cancerous cell lines used in the studies were for pancreatic cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, oesophageal adenocarcinoma, prostrate cancer, colon cancer, breast cancer, gut derived adenocarcinoma, gastric cancer, colorectal cancer, bladder cancer, glioblastoma, histiocytic leukemia, acute myeloid leukemia and non-small cell lung cancer. The reliability of the selected studies was assessed using ToxRTool. Results: Based on this review, guggulsterone significantly affected pancreatic cancer (MiaPaCa-2, Panc-1, PC-Sw, CD18/HPAF, Capan1, PC-3), hepatocellular carcinoma (Hep3B, HepG2, PLC/PRF/5R), head and neck squamous cell carcinoma (SCC4, UM-22b, 1483), cholangiocarcinoma (HuCC-T1, RBE, Sk-ChA-1, Mz-ChA-1) and oesophageal adenocarcinoma (CP-18821, OE19), prostrate cancer (PC-3), colon cancer (HT-29), breast cancer (MCF7/DOX), gut derived adenocarcinoma (Bic-1), gastric cancer (SGC-7901), colorectal cancer (HCT116), bladder cancer (T24, TSGH8301), glioblastoma (A172, U87MG, T98G), histiocytic leukemia (U937), acute myeloid leukemia (HL60, U937) and non-small cell lung cancer (A549, H1975) by inducing apoptotic pathways, inhibiting cell proliferation, and regulating the expression of genes involved in apoptosis. Guggulsterone is known to have therapeutic and preventive effects on various categories of cancers. It can inhibit the progression of tumors and can even reduce their size by inducing apoptosis, exerting anti-angiogenic effects, and modulating various signaling cascades. In vitro studies reveal that Guggulsterone inhibits and suppresses the proliferation of an extensive range of cancer cells by decreasing intrinsic mitochondrial apoptosis, regulating NF-kB/STAT3/ß-Catenin/PI3K/Akt/CHOP pathway, modulating the expression of associated genes/proteins, and inhibiting angiogenesis. Furthermore, Guggulsterone reduces the production of inflammatory markers, such as CDX2 and COX-2. The other mechanism of the Guggulsterone activity is the reversal of P-glycoprotein-mediated multidrug resistance. Twenty three studies were selected for meta-analysis following the PRISMA statements. Fixed effect model was used for reporting the odds ratio. The primary endpoint was percentage apoptosis. 11 of 23 studies reported the apoptotic effect at t = 24 h and pooled odds ratio was 3.984 (CI 3.263 to 4.865, p < 0.001). 12 studies used Guggulsterone for t > 24 h and the odds ratio was 11.171 (CI 9.148 to 13.643, 95% CI, p < 0.001). The sub-group analysis based on cancer type, Guggulsterone dose, and treatment effects. Significant alterations in the level of apoptotic markers were reported by Guggulsterone treatment. Conclusion: This study suggested that Guggulsterone has apoptotic effects against various cancer types. Further investigation of its pharmacological activity and mechanism of action should be conducted. In vivo experiments and clinical trials are required to confirm the anticancer activity.

MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells.

RNA-binding protein Musashi 2 (MSI2) is elevated in several cancers and is linked to poor prognosis. Here, we tested if MSI2 promotes MYC and viral mRNA translation to induce self-renewal via an internal ribosome entry sequence (IRES). We performed RIP-seq using anti-MSI2 antibody in tumor-initiating stem-like cells (TICs). MSI2 binds the internal ribosome entry site (IRES)-containing oncogene mRNAs including MYC, JUN and VEGFA as well as HCV IRES to increase their synthesis and promote self-renewal and tumor-initiation at the post-transcriptional level. MSI2 binds a lncRNA to interfere with processing of a miRNA that reduced MYC translation in basal conditions. Deregulation of this integrated MSI2-lncRNA-MYC regulatory loop drives self-renewal and tumorigenesis through increased IRES-dependent translation of MYC mRNA. Overexpression of MSI2 in TICs promoted their self-renewal and tumor-initiation properties. Inhibition of MSI2-RNA binding reduced HCV IRES activity, viral replication and liver hyperplasia in humanized mice predisposed by virus infection and alcohol high-cholesterol high-fat diet. Together MSI2, integrating the MYC oncogenic pathway, can be employed as a therapeutic target in the treatment of HCC patients. A hypothetical model shows that MSI2 binds and activates cap-independent translation of MYC, c-JUN mRNA and HCV through MSI2-binding to Internal Ribosome Entry Sites (IRES) resulting in upregulated MYC, c-JUN and viral protein synthesis and subsequent liver oncogenesis. Inhibitor of the interaction between MYC IRES and MSI2 reduces liver hyperplasia, viral mRNA translation and tumor formation.

Implication of Lupeol in compensating Sorafenib-induced perturbations of redox homeostasis: A preclinical study in mouse model.

AIMS: Cancer chemotherapeutic drugs can potentially cause several adverse effects that influence a patient's general well-being. Sorafenib, an approved drug used in clinics against multiple cancers whose overall efficacy suffered a serious setback due to various side effects, leading to its frequent discontinuation. Lupeol has recently been considered an important prospective therapeutic agent due to its low toxicity and enhanced biological efficacy. Hence, our study aimed to evaluate whether Lupeol can perturb the Sorafenib-induced toxicity. MAIN METHODS: To test our hypothesis, we studied DNA interaction, level of cytokines, LFT/RFT, oxidant/antioxidant status, and their influences on genetic, cellular, and histopathological changes using both in vitro and in vivo models. KEY FINDINGS: The Sorafenib-treated group showed a marked increase in reactive oxygen and nitrogen species (ROS/RNS), an increase in liver and renal function marker enzymes, serum cytokines (IL-6, TNF-α, IL-1ß) macromolecular damages (protein, lipid, and DNA), and a decrease in antioxidant enzymes (SOD, CAT, TrxR, GPx, GST). Moreover, Sorafenib-induced oxidative stress caused marked cytoarchitectural damage in the liver and kidney and increased p53 and BAX expression. Interestingly, combining Lupeol with Sorafenib improves all the examined toxic insults caused by Sorafenib. In conclusion, our findings suggest that Lupeol can be used in combination with Sorafenib to reduce ROS/RNS-induced macromolecule damage, which might result in hepato-renal toxicity. SIGNIFICANCE: This study presents the possible protective effect of Lupeol against Sorafenib-induced adverse effects by perturbing redox homeostasis imbalance and apoptosis leading to tissue damage. This study is a fascinating finding that warrants further in-depth preclinical and clinical studies.

AURORA KINASE A and related downstream molecules: A potential network for cancer therapy.

Aurora-A kinase (AURKA) belongs to the serine/threonine kinase family specific to cell division. In normal cells, activation of the AURKA protein is essential for regulating chromosomal segregation and centrosome maturation. The physiological concentration of AURKA accumulation has utmost importance during cell division. AURKA starts accumulating during the S phase of the cell cycle, gets functionally activated during the G2/M phase, attaches to the microtubule, and gets degraded during mitotic exit. Overexpression of AURKA could lead to deregulated cell cycle division, which is intrinsic to numerous cancers. Moreover, dysregulated AURKA affects various downstream molecules that aid in cancer pathogenesis. AURKA phosphorylates its substrates, including oncoproteins, transcriptional factors, tumor suppressor proteins, or other kinases central to various oncogenic signaling pathways critical to cancer. Considering the central role of AURKA in cell proliferation and tumorigenesis, targeting AURKA can be a novel alternative to cancer management. Several AURKA inhibitors have shown promising responses against different cancers either as a single agent or combined with various therapies. This chapter briefly discusses the role of AURKA and its downstream molecules in cancer vis-à-vis the role of AURKA inhibitor in chemoprevention.

Neolamarckia cadamba (Roxb.) Bosser (Rubiaceae) extracts: promising prospects for anticancer and antibacterial potential through in vitro and in silico studies.

Neolamarckia cadamba is an Indian traditional medicinal plant having various therapeutic potentials. In the present study, we did solvent-based extraction of Neolamarckia cadamba leaves. The extracted samples were screened against liver cancer cell line (HepG2) and bacteria (Escherichia coli). MTT cytotoxic assay was performed for in vitro analysis of extracted samples against the HepG2 cell lines and the normal human prostate PNT2 cell line. Chloroform extract of Neolamarckia cadamba leaves showed better activity with IC50 value 69 µg/ml. DH5α strain of Escherichia coli (E. coli) was cultured in Luria Bertani (LB) broth media and minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) were calculated. Solvent extract chloroform showed better activity in MTT analysis and antibacterial screening and it was taken for characterization of phytocomposition by Fourier transform infrared (FTIR) and gas chromatography mass spectrometry (GC-MS). The identified phytoconstituents were docked with potential targets of liver cancer and E. coli. The phytochemical 1-(5-Hydroxy-6-hydroxymethyl-tetrahydropyran-2-yl)-5-methyl-1H-pyrimidine-2,4-dione shows highest docking score against the targets PDGFRA (PDB ID: 6JOL) and Beta-ketoacyl synthase 1(PDB ID: 1FJ4) and their stability was further confirmed by molecular dynamics simulation studies.

Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol.

Androgen deprivation therapy is commonly used for the treatment of prostate cancer. Enzalutamide is a next-generation androgen receptor inhibitor, initially approved to treat castration-resistance prostate cancer. Lupeol, a triterpene present in various fruits, vegetables, has anti-oxidant and anti-proliferative activity. The present study aimed to evaluate the Enzalutamide-induced toxicity and its possible amelioration by Lupeol. We performed multiple in vitro and in vivo experiments to conclude our hypothesis. The results revealed that both Enzalutamide and Lupeol interact with DNA through electrostatic interactions. Enzalutamide (5-20 µM) caused cytotoxicity in both normal (PNT2) and cancer cells (LNCaP and 22Rv1). However, Lupeol (10-50 µM) specifically killed the cancer cells while sparing normal cells. The study further revealed that Lupeol could attenuate Enzalutamide-induced cytotoxicity and genotoxicity (chromosomal aberrations and micronucleus formation) to normal cells and potentially induce cytotoxicity to transformed cells. We further observed that Lupeol (40 mg/kg) mediated attenuation of the Enzalutamide (10 mg/kg) induced oxidative and DNA damages. Our study also revealed that Lupeol reverses the Enzalutamide-induced hepatic and renal damages. In conclusion, our study indicates that Lupeol can be used as an adjuvant for reducing the toxic effects and enhancing the effectiveness of Enzalutamide.

Research and Patents Status of Selected Phytochemicals Against Cancer: How Close and How Far?

BACKGROUND: Cancer is a global health issue and economic burden with a continuous increase in incidence and mortality. Over the years, the underlying molecular mechanism of cancers was thoroughly researched, leading to multiple drugs' development. Unfortunately, most drugs have some serious drawbacks, such as therapy resistance and toxicity. Epidemiological studies have shown that a diet rich in fruits and vegetables has cancer prevention properties, which shifted the attention to the potential role of phytochemicals in anti-carcinogenic activity. OBJECTIVE: To review the present status of phytochemicals research and patents in cancer prevention and chemosensitization. METHODS: We explored the relevant published articles and patents to review the phytochemicals showing cancer preventive role in preclinical settings from 1997 onwards. RESULTS: We summarise the role of phytochemicals on anti-carcinogenic, anti-inflammatory, antiproliferative, anti-metastatic, and pro-apoptotic activities in both in vitro and in vivo. Thus, phytochemicals might be an excellent chemosensitizing agent against chemoresistant cells and possibly one of the safest and most effective options for cancer therapy. However, one of the limitations of phytochemicals is their poor bioavailability and rapid excretion. Several analogs have been introduced to increase bioavailability, better biological efficacy, absorption, and retention. In fact, various phytochemicals and their analogs have been patented for their anti-cancerous properties. CONCLUSION: This mini-review discusses various phytochemicals and their anti-cancerous and chemosensitizing roles. Due to their clinical relevance, recent trends in phytochemical extraction and exploration have shown that more and more phytochemicals are being patented.

Protective effects of a polyherbal medicine, Majoon Suranjan against bisphenol-A induced genetic, oxidative and tissue damages.

Bisphenol-A (BPA) is a toxic chemical largely produced and used in polycarbonate plastics worldwide. Majoon Suranjan (MS), a polyherbal formulation, is used as an anti-inflammatory medicine against rheumatoid arthritis. The present study aimed to evaluate BPA-induced toxicity and its possible amelioration by MS. To test our hypothesis, we performed gas chromatography-mass spectrometry (GC-MS) analysis, DNA interaction studies, genotoxicity tests, oxidative stress parameters, and histopathological examinations. GC-MS profiling of MS revealed the presence of various anti-oxidant compounds. DNA interaction studies showed that both chemicals intercalate between DNA base pairs. Next, we observed BPA-induced genotoxicity and oxidative damage. The observed effects might be due to BPA-induced reactive oxygen species production. Further, BPA changed the anti-oxidant enzyme activities, increased the malondialdehyde, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and caused gross damage to the liver and kidney. Interestingly, these effects were significantly reversed by MS. In conclusion, MS shows protective effects against BPA-induced toxicity and could be a potential alternative medicine against BPA toxicity, especially in third-world countries where BPA uses are not strictly regulated.Highlights:Bisphenol-A (BPA) induces multiple toxic effects.BPA induces genotoxicity, oxidative and tissue damage.Majoon Suranjan (MS) ameliorates the BPA induced toxic effects.GC-MS profiling show various active anti-oxidant compounds in MS.MS is anti-genotoxic, anti-oxidant, and hepato-renal protective.

Role of lupeol in chemosensitizing therapy-resistant prostate cancer cells by targeting MYC, ß-catenin and c-FLIP: in silico and in vitro studies.

Prostate cancer (CaP) is one of the most frequent malignancies amongst men. Enzalutamide is the second-generation potent androgen receptor (AR) antagonist used against metastatic and non-metastatic CaP. Unfortunately, the development of chemoresistance in cancer cells reduces the effectiveness of Enzalutamide. Lupeol is a pentacyclic triterpene found in different fruits, vegetables, and medicinal plants and possesses anti-inflammatory and anti-cancer properties. Here, we report in silico and in vitro studies of Lupeol and Enzalutamide against the ß-CATENIN, c-FLIPL, and c-MYC, which play a significant role in chemoresistance. We observed that Lupeol significantly inhibits the cell growth of chemoresistant Du145 cells and cancer stem cells (CSCs) either alone or in combination with Enzalutamide. Lupeol and Enzalutamide were also found to dock with ß-CATENIN, c-FLIPL, and c-MYC. The following MD simulation data showed both compounds exerting structural changes in these proteins. Finally, they significantly inhibit the transcriptional activity of all these genes, as observed by luciferase assay. Thus, we infer that Lupeol chemosensitizes the CaP cells for Enzalutamide-resistant CaP cells.