carnosol and Neoplasms

Despite the newly treatment procedures, cancer is considered as the main health threat nowadays and, therefore, new therapeutic options such as traditional medicine should be investigated. Rosemary (Rosmarinus officinalis L.) has been found to possess antitumor effects due to its major ingredients, including carnosic acid, carnosol, ursolic acid, and rosmarinic acid.. This study was designed to gather the recent literature findings from 2010 to 2016 on the cancer anti-tumor activities of carnosol and probably involved mechanisms.. The online English papers were gathered through various search websites, including PubMed, Iran Medex, Medline, Google Scholar, and Scopus from 2010 to 2016.. Carnosol, the specific composition of rosemary, has been shown to have beneficial effects in keeping humans healthy and may be acted as an antitumor agent.. This review revealed that carnosol may be effective as an anti-tumor agent in the different types of cancer by inducing apoptosis and inhibiting the cell cycle division. However, more studies are needed to confirm carnosol therapeutic effects in human.

Topics: Abietanes; Animals; Antineoplastic Agents; Humans; Neoplasms

For several decades, bioactive phytochemicals have been appreciated to prevent and cure various lethal diseases. Many studies have proven the ability of dietary phytochemicals to avoid and retard tumor initiation and progression. Among the pharmacologically active moieties, terpenoids are considered one of the most important classes. Carnosol, is also a kind of diterpenoid, which known to possess a range of therapeutic effects such as anti-cancer, anti-inflammatory, and anti-oxidant activities. All these effects are mediated via modulating different signaling cascades, including apoptosis regulating molecules (Bax/Bcl2), prosurvival-proproliferative molecules (Akt/mTOR, MAPK), transcription factors like NF-kappaB, STAT3-6, and steroid receptors, such as androgen and estrogen receptors. The present review highlights the recent trends and advancements have been done in the field of research by using carnosol.

Topics: Abietanes; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Cell Proliferation; Humans; Neoplasm Metastasis; Neoplasms; Rosmarinus; Signal Transduction

Recently, rosemary extracts standardized to diterpenes (e.g. carnosic acid and carnosol) have been approved by the European Union (EU) and given a GRAS (Generally Recognized as Safe) status in the United States by the Food and Drug Administration (FDA). Incorporation of rosemary into our food system and through dietary selection (e.g. Mediterranean Diet) has increased the likelihood of exposure to diterpenes in rosemary. In consideration of this, a more thorough understanding of rosemary diterpenes is needed to understand its potential for a positive impact on human health. Three agents in particular have received the most attention that includes carnosic acid, carnosol, and rosmanol with promising results of anti-cancer activity. These studies have provided evidence of diterpenes to modulate deregulated signaling pathways in different solid and blood cancers. Rosemary extracts and the phytochemicals therein appear to be well tolerated in different animal models as evidenced by the extensive studies performed for approval by the EU and the FDA as an antioxidant food preservative. This mini-review reports on the pre-clinical studies performed with carnosic acid, carnosol, and rosmanol describing their mechanism of action in different cancers.

Topics: Abietanes; Animals; Antineoplastic Agents, Phytogenic; Diterpenes; Humans; Neoplasms; Phytotherapy; Plant Extracts; Plants, Medicinal; Rosmarinus; Signal Transduction

Cancer remains an important cause of mortality nowadays and, therefore, new therapeutic approaches are still needed. Rosemary (Rosmarinus officinalis L.) has been reported to possess antitumor activities both in vitro and in animal studies. Some of these activities were attributed to its major components, such as carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Initially, the antitumor effects of rosemary were attributed to its antioxidant activity. However, in recent years, a lack of correlation between antioxidant and antitumor effects exerted by rosemary was reported, and different molecular mechanisms were related to its tumor inhibitory properties. Moreover, supported by the U.S. Food and Drug Administration and the European Food and Safety Authority, specific compositions of rosemary extract were demonstrated to be safe for human health and used as antioxidant additive in foods, suggesting the potential easy application of this agent as a complementary approach in cancer therapy. In this review, we aim to summarize the reported anticancer effects of rosemary, the demonstrated molecular mechanisms related to these effects and the interactions between rosemary and currently used anticancer agents. The possibility of using rosemary extract as a complementary agent in cancer therapy in comparison with its isolated components is discussed.

Topics: Abietanes; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Breast Neoplasms; Cinnamates; Depsides; Drug Interactions; Europe; Humans; Neoplasms; Phytotherapy; Plant Extracts; Rosmarinic Acid; Rosmarinus; Triterpenes; United States; United States Food and Drug Administration; Ursolic Acid

The Mediterranean diet and more specifically certain meats, fruits, vegetables, and olive oil found in certain parts of the Mediterranean region have been associated with a decreased cardiovascular and diabetes risk. More recently, several population based studies have observed with these lifestyle choices have reported an overall reduced risk for several cancers. One study in particular observed an inverse relationship between consumption of Mediterranean herbs such as rosemary, sage, parsley, and oregano with lung cancer. In light of these findings there is a need to explore and identify the anti-cancer properties of these medicinal herbs and to identify the phytochemicals therein. One agent in particular, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals. This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent.

Topics: Abietanes; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Humans; Neoplasms; Signal Transduction

Cancer cachexia is a systemic metabolic disorder syndrome characterized by severe wasting of muscle and adipose tissues while is lack of effective therapeutic approaches. Carnosol (CS) was found in our previous study to exhibit ameliorating effects on cancer cachexia. In the present study, we designed and synthesized 49 CS analogues by structural modification of CS. Results of activity screening revealed that, among the analogues, WK-63 exhibited better effects than CS in ameliorating atrophy of C2C12 myotubes induced by conditioned medium of C26 tumor cells. WK-63 could also dose-dependently alleviate adipocyte lipolysis of mature 3 T3-L1 cells induced by C26 tumor cell conditioned medium. WK-63 alleviated myotube atrophy by inhibiting Nuclear Factor kappa-B (NF-κB) and activating the Protein Kinase B (AKT) signaling pathway, and also alleviated fat loss by inhibiting NF-κB and Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways. Results of pharmacokinetic (PK) assay showed that, compared with other analogues, WK-63 exhibited longer half-life (T

Topics: Adipocytes; AMP-Activated Protein Kinases; Animals; Atrophy; Cachexia; Culture Media, Conditioned; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-akt

Cancer-derived exosomes are involved in the development of cancer cachexia. Carnosol, which exhibited ameliorating effects on cancer cachexia of C26 tumour-bearing mice in our previous study, alleviated atrophy of C2C12 myotubes induced by exosomes of C26 tumour cells in the present study. MiR-183-5p was found to be rich in C26 cells and C26 exosomes, and miR-183-5p mimic could directly induce atrophy of C2C12 myotubes. Carnosol at 5 to 20 μM could dose-dependently ameliorate the myotube atrophy induced by miR-183-5p. Four and a half LIM domain protein 1 (FHL1) was shown to be the direct target of miR-183-5p. Increase in myostatin, p-Smad3, MuRF-1, Atrogin-1, HIF-1α and p-STAT3 and decrease in mitochondrial respiration were also induced by miR-183-5p mimic in C2C12 myotubes. Carnosol could not affect the decrease in FHL-1 and the activation of STAT3 pathway but could significantly alleviate the increase in myostatin, p-Smad3, MuRF-1, Atrogin-1 and the decrease in mitochondrial respiration induced by miR-183-5p. The protective effects of carnosol on myotubes against atrophy of C2C12 myotubes induced by miR-183-5p, based on both its inhibiting effects on MuRF-1 and Atrogin-1-mediated protein degradation and its ability of keeping the mitochondrial respiration, might contribute to its ameliorating effects on cancer cachexia.

Topics: Abietanes; Animals; Atrophy; Cachexia; Cell Line, Tumor; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Mice; MicroRNAs; Muscle Fibers, Skeletal; Muscle Proteins; Myostatin; Neoplasms

Cancer cachexia is a multifactorial debilitating syndrome that directly accounts for more than 20% of cancer deaths while there is no effective therapeutic approach for treatment of cancer cachexia. Carnosol (CS) is a bioactive diterpene compound present in Lamiaceae spp., which has been demonstrated to have antioxidant, anti-inflammatory, and anticancer properties. But its effects on cancer cachexia and the possible mechanism remain a mystery.. The in vitro cell models of C2C12 myotube atrophy and 3T3-L1 mature adipocyte lipolysis were used to check the activities of CS and its synthesized analogues. C26 tumour-bearing BALB/c mice were applied as the animal model to examine their therapeutic effects on cancer cachexia in vivo. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms.. Carnosol and its analogues [dimethyl-carnosol (DCS) and dimethyl-carnosol-D6 (DCSD)] alleviated myotube atrophy of C2C12 myotubes and lipolysis of 3T3-L1 adipocytes in vitro. Interestingly, CS and its analogues exhibited stronger inhibitive effects on muscle atrophy induced by tumour necrosis factor-α (TNF-α) (CS, P < 0.001; DCS, P < 0.001; DCSD, P < 0.001) in C2C12 myoblasts than on muscle atrophy induced by IL-6 (CS, P < 0.05; DCS, P = 0.08; DCSD, P < 0.05). In a C26 tumour-bearing mice model, administration of CS or its analogue DCSD significantly prevented body weight loss without affecting tumour size. At the end of the experiment, the body weight of mice treated with CS and DCSD was significantly increased by 11.09% (P < 0.01) and 11.38% (P < 0.01) compared with that of the C26 model group. CS and DCSD also improved the weight loss of epididymal adipose tissue in C26 model mice by 176.6% (P < 0.01) and 48.2% (P < 0.05) increase, respectively. CS and DCSD treatment partly preserved gastrocnemius myofibres cross-sectional area. CS treatment decreased the serum level of TNF-α (-95.02%, P < 0.01) but not IL-6 in C26 tumour-bearing mice. Inhibition on NF-κB and activation of Akt signalling pathway were involved in the ameliorating effects of CS and its analogues on muscle wasting both in vitro and in vivo. CS and its analogues also alleviated adipose tissue loss by inhibiting NF-κB and AMPK signalling pathways both in vitro and in vivo.. CS and its analogues exhibited anticachexia effects mainly by inhibiting TNF-α/NF-κB pathway and decreasing muscle and adipose tissue loss. CS and its analogues might be promising drug candidates for the treatment of cancer cachexia.

Topics: Abietanes; Animals; Cachexia; Lipolysis; Mice; Mice, Inbred BALB C; Muscular Atrophy; Neoplasms

Abietane diterpenes exhibit an array of interesting biological activities, which have generated significant interest among the pharmacological community. Starting from the abietane diterpenes carnosic acid and carnosol, twenty four new triazole derivatives were synthesized using click chemistry. The compounds differ in the length of the linker and the substituent on the triazole moiety. The compounds were assessed as antiproliferative and antifungal agents. The antiproliferative activity was determined on normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells while the antifungal activity was assessed against Candida albicans ATCC 10231 and Cryptococcus neoformans ATCC 32264. The carnosic acid γ-lactone derivatives 1-3 were the most active antiproliferative compounds of the series, with IC50 values in the range of 43.4-46.9 μM and 39.2-48.9 μM for MRC-5 and AGS cells, respectively. Regarding antifungal activity, C. neoformans was the most sensitive fungus, with nine compounds inhibiting more than 50% of its fungal growth at concentrations ≤250 µg∙mL-1. Compound 22, possessing a p-Br-benzyl substituent on the triazole ring, showed the best activity (91% growth inhibition) at 250 µg∙mL-1 In turn, six compounds inhibited 50% C. albicans growth at concentrations lower than 250 µg∙mL-1.

Topics: Abietanes; Antifungal Agents; Candida albicans; Cell Line, Tumor; Cell Proliferation; Click Chemistry; Cryptococcus neoformans; Fibroblasts; Humans; Microbial Sensitivity Tests; Neoplasms; Plant Extracts; Structure-Activity Relationship; Triazoles

To explore whether glutathione (GSH) increased through Nrf-2 activation is involved in the cytoprotective effects of carnosol in HepG2 cells.. Human hepatoma cell line HepG2 were exposed to rosemarry essential oil or carnosol. Cell viability was measured using an Alamar blue assay. The production of intracellular GSH was determined using monochlorobimane. The level of protein or mRNA was examined by Western blotting or RT-PCR, respectively.. Rosemarry essential oil (0.005%-0.02%) and carnosol (5 and 10 mol/L) increased the intracellular GSH levels and GSH synthesis enzyme subunit GCLC/GCLM expression. Rosemary essential oil and carnosol increased nuclear accumulation of Nrf2 and enhanced Nrf2-antioxidant responsive element (ARE)-reporter activity. Transfection of the treated cells with an Nrf2 siRNA construct blocks GCLC/GCLM induction. Furthermore, pretreatment of the HepG2 cells with essential oil and carnosol exerted significant cytoprotective effects against H(2)O(2) or alcohol. In TNFα-treated cells, the nuclear translocation and transcriptional activity of NF-κB was abolished for 12 h following carnosol pretreatment. Cotreatment with GSH also suppressed NF-κB nuclear translocation, whereas cotreatment with BSO, a GSH synthesis blocker, blocked the inhibitory effects of carnosol.. This study demonstrated that Nrf2 is involved in the cytoprotective effects by carnasol, which were at least partially mediated through increased GSH biosynthesis.

Topics: Abietanes; Antineoplastic Agents, Phytogenic; Cell Survival; Cytoprotection; Ethanol; Glutathione; Hep G2 Cells; Humans; Neoplasms; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Plant Oils; Rosmarinus; Tumor Necrosis Factor-alpha; Up-Regulation