An Insight into Anticancer Effect of Propolis and Its Constituents: A Review of Molecular Mechanisms.

Propolis is a natural compound collected by honeybees from different parts of plants. Honeybees produce a sticky component besides honey by mixing the tree resin and other botanical sources with saliva called propolis or bee glue. Propolis was traditionally used as a wound healing substance, cosmetic, medicine, and many other conditions. Till now, there is no definite curable treatment for most cancers and chemotherapeutic drugs and drugs used for targeted therapies have serious side effects. According to a recent research, natural products are becoming increasingly essential in cancer prevention. Natural products are a great source of potential therapeutic agents, especially in the treatment of cancer. Previous studies have reported that the presence of caffeic acid phenethyl ester (CAPE), artepillin C, and chrysin is responsible for the anticancer potential of propolis. Most of the previous studies suggested that propolis and its active compounds inhibit cancer progression by targeting multiple signaling pathways including phosphoinositide 3-kinases (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling molecules, and induce cell cycle arrest. Induction of apoptosis by propolis is mediated through extrinsic and intrinsic apoptotic pathways. The aim of this review is to highlight and summarize the molecular targets and anticancer potential of propolis and its active compounds on cell survival, proliferation, metastasis, and apoptosis in cancer cells.

Molecular Targets of Nimbolide for Anti-Cancer Therapy: An Updated Review.

Cancer is a major cause of death worldwide with an increasing incidence rate and is considered a major public health problem. Distance metastasis to other tissues, high toxicity, and drug resistance of cancer cells to chemotherapy demand novel therapeutic approaches to treat cancer. Natural compounds from medicinal plants have been studied for therapeutic use in various malignancies. Nimbolide is an active principal compound from Azadirachta indica, which is an Asian traditional medicinal plant utilized historically as a remedy for a variety of diseases due to its antioxidant, anti-inflammatory, anti-cancer, and antimicrobial properties. It is a limonoid triterpene possessing potent anti-cancer effects in various types of cancers. It has been reported to induce multiple cytotoxic effects in tumor cells by modulating the cell proliferation, cell cycle, apoptosis, and metastasis by altering the various molecular signaling pathways. In the present review, we summarized all the in vitro and in vivo studies reporting the molecular targets of nimbolide for the therapeutic approaches in different types of cancer cells. We analyzed research publications up to September 2021 on the effect of nimbolide in various malignancies and the molecular mechanism of action. Nimbolide targets different signaling pathways including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), insulin like growth factor (IGF), Wingless and INT-1 (Wnt)/ß-catenin, mitogen-activated protein kinases (MAPK)/c-Jun N-terminal kinases (JNK), phosphoinositide 3-kinase (PI3K)/AKT, tumor necrosis factor-α (TNF-α)/nuclear factor kappa B (NF-κß), and death receptor 5 (DR5) in several cancer cells. Nimbolide's widespread availability and absence of side effects, as well as understanding the molecular mechanism of nimbolide's action, will be useful to develop a therapeutic agent against cancer.

Antioxidant mediated ameliorative steroidogenesis by Commelina benghalensis L. and Cissus quadrangularis L. against quinalphos induced male reproductive toxicity.

Quinalphos (QP) is speculated to cause endocrine disruption through the generation of reactive oxygen species (ROS) by oxidative stress (OS). Exposure of QP decreased testosterone level considerably which resulted in reduced viable sperms in mice. The QP induced toxicity is initiated by the formation of free radicals as it is evidenced from the increased Lipid peroxidation (LPO) and diminution of antioxidant enzymes in testicular tissue. Increased serum cholesterol and reduced testicular cholesterol indicated the inhibition of cholesterol transport and biosynthesis in testicular tissues. Lack of cholesterol in testicular tissue impaired the steroidogenesis by down-regulating the expression of StAR protein, Cytochrome P450, 3ß-HSD and 17ß-HSD leading to reduced testosterone level. Treatment of Commelina benganlensis (CBE) and Cissus quadrangularis (CQE) significantly recovered the alterations in antioxidant profiles as well as increased LPO, thereby recovering the decreased mRNA expression levels of intermediate enzymes. However, CQE effectively protected the OS and prevented the inhibition of steroidogenesis thereby preventing male infertility.

Review on molecular and chemopreventive potential of nimbolide in cancer.

Cancer is the most dreaded disease in human and also major health problem worldwide. Despite its high occurrence, the exact molecular mechanisms of the development and progression are not fully understood. The existing cancer therapy based on allopathic medicine is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a non-toxic and effective mode of treatment is needed to control cancer development and progression. Some medicinal plants offer a safe, effective and affordable remedy to control the cancer progression. Nimbolide, a limnoid derived from the neem (Azadirachta indica) leaves and flowers of neem, is widely used in traditional medical practices for treating various human diseases. Nimbolide exhibits several pharmacological effects among which its anticancer activity is the most promising. The previous studies carried out over the decades have shown that nimbolide inhibits cell proliferation and metastasis of cancer cells. This review highlights the current knowledge on the molecular targets that contribute to the observed anticancer activity of nimbolide related to induction of apoptosis and cell cycle arrest; and inhibition of signaling pathways related to cancer progression.

Impact of lycopene on epididymal androgen and estrogen receptors' expression in polychlorinated biphenyls-exposed rat.

The aim of the study was to evaluate the androgen (AR) and estrogen receptors' (ER) expression in epididymis of polychlorinated biphenyls (PCBs)-exposed rats. The rats were assigned to groups. Group I controls were treated with corn oil 80 µL/d intraperitoneally (ip), group II were treated with 2 mg/kg/d of A1254 ip; and group III were treated with 2 mg/kg/d of A1254 ip along with simultaneous oral supplementation of 4 mg/kg/d lycopene . The treatment was given daily for 30 days. After 24 hours of treatment, the rats were killed, and the epididymal regions (caput, corpus, and cauda) were dissected out, weighed, and prepared to estimate the levels of sialic acid, glyceryl phosphoryl choline (GPC), hydrogen peroxide (H2O2), and lipid peroxidation (LPO). The messenger RNA (mRNA) expressions of AR, ERα, and ERß were analyzed by reverse transcriptase-polymerase chain reaction, and ERα and ERß protein expressions were analyzed by immunoblotting. The toxicity of PCBs was also confirmed by histology. There was a marked decrease in epididymal weight, sialic acid, and GPC levels, while oxidative stress markers H2O2 and LPO were increased in PCBs-treated rats. The mRNA and protein expression of AR, ERα, and ERß were decreased in PCBs-treated groups, and the histology confirms the cytoplasmic damage in the regions of caput, corpus, and cauda in PCBs-treated rats. Simultaneous supplementation of lycopene to PCBs-exposed rats resulted in significant decrease in the oxidative stress markers as that of control, while the AR, ERα, and ERß gene expressions were near to control. The results suggest that lycopene has ameliorative effect against PCBs-induced toxicity in epididymis.

Protective effect of zinc on N-methyl-N-nitrosourea and testosterone-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley rats.

Previous studies have suggested that zinc exerts anticarcinogenic and antiproliferative effects against prostate cancer both in vitro and in rat ventral prostate. Zinc accumulation diminishes early in the course of prostate malignancy and it inhibits the growth of several carcinoma cells through induction of cell cycle arrest and apoptosis. In this study, we have investigated the influence of zinc on N-methyl-N-nitrosourea (MNU) and testosterone (T)-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley (SD) rats. The results indicate that zinc plays an important role in prostate carcinogenesis. Increased tumor incidence was accompanied by a decrease in prostatic acid phosphatase activity, citrate, zinc, glutathione-S-transferase, reduced glutathione, p53, B-cell lymphoma protein (Bcl-2)-associated X protein and caspase-3 levels in MNU + T-treated rats. On the contrary, significantly increased phase I drug metabolizing enzyme activities, lipid peroxide, hydrogen peroxide, proliferating cell nuclear antigen, Bcl-2 and Bcl-X(L) protein levels were observed in the dorsolateral prostate of MNU + T-treated rats. Simultaneous zinc supplementation significantly reversed these effects in MNU + T-treated rats. Signs of dysplasia, a characteristic of prostatic intraepithelial neoplasia, were evident in the dorsolateral prostatic tissue sections by MNU + T administration. However, zinc supplementation has reversed these effects in the dorsolateral prostatic histoarchitecture. These results suggest that zinc may act as an essential trace element against MNU and testosterone-induced prostatic preneoplastic progression in SD rats.

Induction of apoptosis and inhibition of PI3K/Akt pathway in PC-3 and LNCaP prostate cancer cells by ethanolic neem leaf extract.

AIM OF THE STUDY: The present study is aimed to delineate the effect of ethanolic neem leaf extract on PI3K/Akt and apoptotic pathway in prostate cancer cell lines (PC-3 and LNCaP). MATERIALS AND METHODS: To test the hypothesis, two different prostate cancer cell lines LNCaP (androgen dependent) and PC-3 (androgen independent) were taken. Cells were exposed to various concentrations of ethanolic neem leaf extract (ENLE) (25-125 µg/ml). The doses were fixed by cell viability (MTT) assay. For apoptotic detection in situ apoptosis assay, caspase-3 activity and protein expression of cytochrome c and Poly-ADP Ribose Polymerase (PARP) were analysed as well as mRNA expression of Bcl-2 family proteins was studied by RT-PCR. The phosphoinositide 3-kinase (PI3K) and p-Akt were analysed by western blotting and mRNA expression of Akt 1 and 2, PTEN was performed by RT-PCR. Immunoblotting of cyclin D1 and p21 was done to access the inhibition of cell proliferation. RESULTS: ENLE gives 50% inhibition at a dose of 100 µg/ml in both PC-3 and LNCaP cells and considered as effective dose. ENLE decreased the protein expression of PI3K as well as p-Akt and the mRNA expression of Akt 1and 2 in both the cells. There was a significant decrease in mRNA expression of PTEN in LNCaP cells. ENLE induced apoptosis and inhibited cell proliferation by inhibiting PI3K/Akt pathway. Decrease in p-Akt leads to increase in the protein level of Bad, p21 and decrease in the cyclin D1, respectively. ENLE treatment increased the cytochrome c expression and caspase-3 activity as well as regulated the mRNA expression of Bcl-2 family proteins thereby inducing apoptosis to both the cell lines. In situ apoptosis assay showed increased red fluorescence in 100 µg/ml of ENLE in both PC-3 and LNCaP cell lines. CONCLUSIONS: The results suggested that ENLE induces apoptosis and inhibits cell proliferation through inhibiting PI3K/Akt pathway in both PC-3 and LNCaP cells.

Studies on the protective role of lycopene against polychlorinated biphenyls (Aroclor 1254)-induced changes in StAR protein and cytochrome P450 scc enzyme expression on Leydig cells of adult rats.

Polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental contaminants that disturb normal endocrine functions, including gonadal functions in humans and mammals. PCBs (Aroclor 1254) - induced toxic manifestations are associated with the production of free radicals. Lycopene belongs to the group of natural carotenoids, which are found in many fruits, vegetables and other green plants. Lycopene, the most potent antioxidant protects against oxidative damage. The present study was conducted to elucidate the protective role of lycopene against Aroclor 1254-induced changes in Leydig cellular steroidogenic acute regulatory (StAR) protein, cytochrome P450 side chain cleavage (P450 scc) enzyme expression and 3beta-hydroxy steroid dehydrogenase (3beta-HSD) activity. The rats were divided into four groups. Each group consists of six animals. Group I rats were administered with corn oil intraperitoneally (i.p.) for 30 days. Group II rats were treated with Aroclor 1254 (i.p.) 2mgkg(-1)body weight (bwt)day(-1) for 30 days. Group III rats were treated with Aroclor 1254 (i.p.) 2mgkg(-1)bwtday(-1) along with simultaneous supplementation of lycopene 4mgkg(-1)bwtday(-1) (gavage) for 30 days. Group IV rats administered with lycopene alone at the dose of 4mgkg(-1)bwt day(-1) (gavage) for 30 days. After 24h of the last treatment, animals were decapitated, blood was collected and serum testosterone level was estimated by radioimmunoassay (RIA). Testes were removed and Leydig cells were isolated in aseptic condition. StAR protein, cytochrome P450 scc enzyme expression were studied by Western blot analysis and 3beta-HSD activity was estimated spectrophotometrically. Aroclor 1254 treatment significantly reduced the serum testosterone level. Simultaneous supplementation of lycopene maintained the serum testosterone to near normal. Aroclor 1254 exposure decreased Leydig cellular StAR protein, cytochrome P450 scc enzyme expression and activity of 3beta-HSD. However, simultaneous supplementation of lycopene improved Leydig cellular StAR protein, cytochrome P450 scc expression and activity of 3beta-HSD. These results suggested that lycopene have ameliorative role against Aroclor 1254 induced Leydig cell dysfunction.