Corosolic acid impairs tumor development and lung metastasis by inhibiting the immunosuppressive activity of myeloid-derived suppressor cells
Horlad H, Fujiwara Y, Takemura K, et al. Molecular Nutrition & Food Research. 2013 DOI: 10.1002/mnfr.201200610
Recent studies demonstrated that myeloid cells are associated with systemic immunosuppression in tumor-bearing hosts. In particular, myeloid cells positive for Gr-1 and CD11b in tumor-bearing mice are called myeloid-derived suppressor cells (MDSC) because of their suppression of T-cell activation. In this study, we investigated the antitumor effects of corosolic acid (CA) in murine sarcoma model.
The results from the in vivo study showed that CA administration did not suppress the tumor proliferation index, but significantly impaired subcutaneous tumor development and lung metastasis. Furthermore, CA administration inhibited signal transducer and activator of transcription-3 (Stat3) activation and increased in the number of infiltrating lymphocytes in tumor tissues. Ex vivo analysis demonstrated that a significant immunosuppressive effect of MDSC in tumor-bearing mice was abrogated and the mRNA expressions of cyclooxygenase-2 and CCL2 in MDSC were significantly decreased by CA administration. Furthermore, CA enhanced the antitumor effects of adriamycin and cisplatin in in vitro.
Since Stat3 is associated with tumor progression not only in osteosarcoma, but also in other malignant tumors, our findings indicate that CA might be widely useful in anticancer therapy by targeting the immunosuppressive activity of MDSC and through its synergistic effects with anticancer agents.
Corosolic acid is a substance extracted from Lagerstroemia speciosa L. and has been reported to have biological activities in in vitro and experimental animal studies, particularly due to its influence on blood sugar. Thus, corosolic acid may have an influence on diabetes. Corosolic acid is found in many plants, particularly banaba, but also in almond hulls, Weigela subsessilis, Perilla frutescens, Campsis grandiflora and other herbs.
Corosolic acid (2alpha,3beta-dihydroxyurs-12-en-28-oic acid) is a pentacyclic triterpene and inhibits glycogen phosphorylases.
Corosolic acid induces apoptosis through mitochondrial pathway and caspases activation in human cervix adenocarcinoma HeLa cells.
Xu et al investigated the response of human cervix adenocarcinoma HeLa cells to Corosolic acid (CRA) treatment. Our results showed that CRA significantly inhibited cell viability in both a dose- and a time-dependent manner. CRA treatment induced S cell-cycle arrest and caused apoptotic death in HeLa cells. We found that CRA increased in Bax/Bcl-2 ratios by up-regulating Bax expression, disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm. Moreover, CRA treatment triggered the activation of caspase-8, -9 and -3 in HeLa cells. All these results indicate that CRA-induced apoptosis is associated with the activation of caspases via a mitochondrial pathway. Taken together, we believe that CRA could have strong potentials for clinical application in treating human cervix adenocarcinoma and improving cancer chemotherapy.
Xu, Y-F., Ge, R-L., Du, J., Xin, H-L., Yi, T-J., Sheng, J-Y., Yongzi Wang, Y-Z. & Ling, C-Q. Corosolic acid induces apoptosis through mitochondrial pathway and caspases activation in human cervix adenocarcinoma HeLa cells. Cancer Letters. Volume 284, Issue 2, Pages 229-237 (1 November 2009)
Corosolic acid Inhibits Glioblastoma Cell Proliferation by Suppressing the Activation of STAT3 and NF-κB in Tumor Cells and Tumor-associated Macrophages
Tumour-associated macrophages (TAMs) of M2 phenotype promote tumour proliferation and are associated with a poor prognosis in patients with glioblastoma. We screened the natural compounds possessing an inhibitory effect on M2 polarisation in human monocyte-derived macrophages. Among 130 purified natural compounds examined, corosolic acid significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, as well as suppressed the secretion of IL-10, one of the anti-inflammatory cytokine preferentially produced by M2 macrophages, thus suggesting that corosolic acid suppresses M2 polarisation of macrophages. Furthermore, corosolic acid inhibited the proliferation of glioblastoma cells, U373 and T98G, and the activation of Signal transducer and activator of transcription-3 (STAT3) and Nuclear Factor-kappa B (NF-κB) in both human macrophages and glioblastoma cells. These results indicate that corosolic acid suppresses the M2 polarisation of macrophages and tumour cell proliferation by inhibiting both STAT3 and NF-κB activation. Therefore, corosolic acid may be a potentially new tool for tumour prevention and therapy.
Fujiwara, Y., Komohara, Y., Ikeda, T. & Takeya, M. Corosolic acid Inhibits Glioblastoma Cell Proliferation by Suppressing the Activation of STAT3 and NF-κB in Tumour Cells and Tumour-associated Macrophages. Cancer Science. DOI: 10.1111/j.1349-7006.2010.01772.x
Corosolic Acid. Scientific Name(s): 2 alpha-hydroxy ursolic acid
Activation of AMP-activated protein kinase on human gastric cancer cells by apoptosis induced by corosolic acid isolated from Weigela subsessilis
Corosolic acid is one of the triterpenoids present in the leaves of Weigela subsessilis. The antidiabetic activity of corosolic acid has been reported previously, but to date, the anticancer effects on gastric cancer have been poorly studied. In this study, corosolic acid showed growth inhibition on SNU-601 human gastric cancer cells, with an IC50 value of 16.9 ± 2.9 μm. Corosolic acid also triggered the activation of caspase-3 and poly (ADP-ribose) polymerase, while it was recovered by Z-VAD-FMK. Moreover, the cell growth/apoptosis activities of corosolic acid were regulated by the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signals. These results showed that corosolic acid-mediated AMPK activation leads to inhibition of mTOR, thus providing a possible mechanism of action of corosolic acid in the inhibition of cancer cell growth and the induction of apoptosis.
Lee MS, Lee CM, Cha EY, Thuong PT, Bae KH, Song IS, Noh SM & Young Sul JY. Phytotherapy Research. 17 JUN 2010. DOI: 10.1002/ptr.3210
Corosolic Acid Dosing
Numerous commercial formulations are available, including tablets, capsules, hypoglycemic food products, and cosmetics. Most formulations are available in capsule form, containing 18% corosolic acid and derived from Lagerstroemia speciosa L. Manufacturer suggested dosage is 1 softgel by mouth 30 minutes before morning and evening meals. Softgel products are marketed for noninsulin dependent type 2 diabetic patients.
Avoid use with hypersensitivity to any of the plant sources of corosolic acid.
Corosolic Acid Interactions
Counsel patients with diabetes or those taking antidiabetic medications about potential additive effects if they are self-medicating with any oral corosolic dietary supplement.
Corosolic Acid Adverse Reactions
There is potential for skin rashes because the product may be derived from several plant species.
Toxicologic information regarding use in humans is lacking.
Corosolic acid is found in numerous plant species, including L. speciosa L., Tiarella polyphylla D. Don, Datisca cannabina L., Eriobotrya japonica (Thunb.) Lindl., and Perilla frutescens (L.) Britton.
Corosolic acid has numerous biological properties including antidiabetic, anti-inflammatory, antiproliferative, and protein kinase C inhibition activity. 1 , 2 It is found in numerous plants species, particularly L. speciosa . 3 Most medical research focuses on the compound's efficacy in diabetes. Glucosol (or GlucoFit ) is a commercially available product primarily marketed in Japan and the United States as a dietary supplement for weight loss and blood sugar balance. 1 Corosolic acid is found in numerous cosmetic products, including creams, lotions, hair tonics, as well as in hypoglycemic health foods. 3 , 4 , 5
Corosolic acid is a naturally occurring pentacyclic triterpene also known as 2 alpha-hydroxy ursolic acid. 6 , 7 Chemical analyses focus on the study of corosolic acid and its derivatives as inhibitors of glycogen phosphorylases for potential development of antidiabetic agents. 1 , 6 There is documented commercial interest in improving the chemical production of corosolic acid and its esters. 8 , 9
Corosolic Acid Uses and Pharmacology Cancer
In vitro data
Corosolic acid has cytotoxic activity against several human cancer cell lines. The compound antagonized morphological modification of K-562 leukemic cells. The mechanism of action may be associated with suppression of protein kinase C activity. 10 In addition, cytotoxic activity has been documented against human cancer cell lines HL-60 (leukemia carcinoma), MCF-7 (breast carcinoma), and Hep-G2 (hepatic carcinoma). 11
In a 2-stage Berenblum experiment on mouse skin papillomas, the inhibitory effect of corosolic acid was comparable or equivalent to beta-carotene, rosmarinic acid, and alpha-linolenic acid. 12
Corosolic acid may improve the insulin pathway. The action of insulin is mediated by tyrosine phosphorylation and initiated by the binding of insulin to the insulin receptor. Corosolic acid may act as an insulin sensitizer, enhancing insulin receptor B phosphorylation indirectly by inhibiting certain nonreceptor protein tyrosine phosphatases. 13 Corosolic acid may also enhance GLUT4 glucose transporter processing of glucose uptake into muscle cells. 14 Another study reported that corosolic acid inhibited gluconeogenesis by increasing the production of the gluconeogenic intermediate fructose-2,6-bisphosphate in isolated hepatocytes. Corosolic acid may promote glycolysis. 15 , 16
Numerous animal experiments document the effect of corosolic acid on blood glucose. One study in rats found that 1% corosolic acid reduced blood glucose levels at 90 minutes after oral administration. 17 Treatment with corosolic acid lowered plasma insulin levels and reduced the blood glucose levels in KK-Ay mice 2 weeks after a single oral dose of 2 mg/kg. Blood glucose in KK-Ay mice treated with corosolic acid decreased in an insulin tolerance test. 18 Another experiment showed similar inhibitory action against increasing blood glucose levels. 19 Increasing the concentration of corosolic acid may lead to enhanced glucose uptake activity. 20 Corosolic acid induced muscle GLUT4 translocation from low-density microsomal membrane to plasma membrane in genetically-induced type 2 diabetic mice. 14 , 16
In a small randomized clinical trial, 10 patients with type 2 diabetes were treated with an extract from the leaves of L. speciosa standardized to 1% corosolic acid ( Glucosol ). Patients receiving Glucosol 32 or 48 mg daily for 2 weeks demonstrated a significant reduction in blood glucose levels. The softgel capsule formulation resulted in a 30% decrease, compared with 20% decrease in blood glucose levels in patients receiving the dry-powder, hard-gelatin capsule formulation. The softgel formulation has better bioavailability, and the active lipophilic triterpene ingredient is better absorbed in an oil-based, soft-gelatin capsule formulation. 21
In a study completed in Japan with 31 patients, corosolic acid lowered postchallenge plasma glucose levels. 22
Other pharmacologic activity
Corosolic acid enhanced the activity of treatment with tobramycin against Pseudomonas aeruginosa in a biofilm inhibition assay. 23
Activity against the classical pathway of the complement system is documented for corosolic acid. 24
In an animal model on metabolic syndrome, corosolic acid had antihypertensive, lipid-lowering, antioxidant, and anti-inflammatory effects on rats. 25 In a similar study, corosolic acid reduced blood pressure and serum-free fatty acid levels in rats. 26
There is in vitro evidence for corosolic acid inhibiting protein tyrosine phosphatase 1B; inhibition of this phosphatase is proposed as a therapy for obesity. 27 Corosolic acid is also a pancreatic lipase inhibitor, the main enzyme for lipid absorption. 28 In a mouse study, corosolic acid acted as a peroxisome proliferator-activated receptor alpha agonist, regulating lipid metabolism and increasing fatty acid beta-oxidation in the liver. 29
Numerous commercial formulations are available, including tablets, capsules, hypoglycemic food products, and cosmetics. Most formulations are available in capsule form containing 18% corosolic acid extracted from L. speciosa . The manufacturer suggested dosage is 1 softgel by mouth 30 minutes before morning and evening meals. Softgel products are marketed for noninsulin dependent type 2 diabetic patients. 30 , 31 , 32
Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.
Counsel patients with diabetes or those taking diabetic medications about the potential additive effects if they are self-medicating with any corosolic oral dietary supplement.
Avoid use with hypersensitivity to any source plants for corosolic acid.
Because the product may be derived from several plant species, there is a potential for skin rashes.
A single oral dose toxicity study in rats administered Glucosol 5 g/kg showed no marked pathological findings. 33
1. Wen X, Sun H, Liu J, et al. Pentacyclic triterpenes. Part 1: The first examples of naturally occurring pentacyclic triterpenes as a new class of inhibitors of glycogen phosphorylases. Bioorg Med Chem Lett . 2005;15(22):4944-4948.
2. Jung M, Park M, Lee HC, Kang YH, Kang ES, Kim SK. Antidiabetic agents from medicinal plants. Curr Med Chem . 2006;13(10):1203-1218.
3. Washino T, Kato Y, Zeida M, Minami H, inventors. Hypoglycemic banaba ( Lagerstroemia speciosa ) extracts. US patent 2005-JP7255. April 14, 2004.
4. Nojima J, Miyake Y, Ohto N, inventors. Hair cosmetics containing corosolic acid. US patent 2006-JP302560. February 14, 2006.
5. Nojima J, Miyake Y, Oto N, Dohi K, inventors; Jpn. Kokai Tokkyo Koho. Cosmetics containing corosolic acid and their uses. US patent 2006-37114. February 14, 2006.
6. Wen X, Xia J, Cheng K, et al. Pentacyclic triterpenes. Part 5: Synthesis and SAR study of corosolic acid derivatives as inhibitors of glycogen phosphorylases. Bioorg Med Chem Lett . 2007;17(21):5777-5782.
7. Aguirre MC, Delporte C, Backhouse N, et al. Topical anti-inflammatory activity of 2 alpha-hydroxy pentacyclic triterpene acids from the leaves of Ugni molinae . Bioorg Med Chem . 2006;14(16):5673-5677.
8. Takayama H, Kitajima M, Ishizuka T, Seo S, inventors. Process for producing corosolic acid. US patent 2004-866733. June 15, 2004.
9. Matsuyama F, Seino Y, Fukushima M, Miura T, Fujita T, Kaneko T, inventors. Early insulin secretion promoters containing corosolic acid and maslinic acid derivatives, and manufacture thereof. US patent 2004-JP13848. September 22, 2004.
10. Ahn KS, Hahm MS, Park EJ, Lee HK, Kim IH. Corosolic acid isolated from the fruit of Crataegus pinnatifida var. psilosa is a protein kinase C inhibitor as well as a cytotoxic agent. Planta Med . 1998;64(5):468-470.
11. Akihisa T, Kama S, Uchiyama T, et al. Cytotoxic activity of Perilla frutescens var. japonica leaf extract is due to high concentractions of oleanolic and ursolic acids. J Nat Med . 2006;60(4):331-333.
12. Banno N, Akihisa T, Tokuda H, et al. Triterpene acids from the leaves of Perilla frutescens and their anti-inflammatory and antitumor-promoting effects. Biosci Biotechnol Biochem . 2004;68(1):85-90.
13. Shi L, Zhang W, Zhou YY, et al. Corosolic acid stimulates glucose uptake via enhancing insulin receptor phosphorylation. Eur J Pharmacol . 2008;584(1):21-29.
14. Miura T, Itoh Y, Kaneko T, et al. Corosolic acid induces GLUT4 translocation in genetically type 2 diabetic mice. Biol Pharm Bull . 2004;27(7):1103-1105.
15. Yamada K, Hosokawa M, Fujimoto S, et al. Effect of corosolic acid on gluconeogenesis in rat liver. Diabetes Res Clin Pract . 2008;80(1):48-55.
16. Klein G, Kim J, Himmeldirk K, Cao Y, Chen X. Antidiabetes and anti-obesity activity of Lagerstroemia speciosa . Evid Based Complement Alternat Med . 2007;4(4):401-407.
17. Hamamoto S, Kogami H, Kohata K, Moriwaki M, Kanada H, Matsuyama F. Glucosol effect on blood glucose in rats. Yakuri to Chiryo . 1999;27(6):1075-1077.
18. Miura T, Ueda N, Yamada K, et al. Antidiabetic effects of corosolic acid in KK-Ay diabetic mice. Biol Pharm Bull . 2006;29(3):585-587.
19. Matsuyama F, Seino Y, Yamada Y, et al. Corosolic acid and its analogs as oral gluconeogenesis inhibiting agents. US patent WO2005-JP8569. April 28, 2005.
20. Zong W, Zhao G. Corosolic acid isolation from the leaves of Eriobotrta japonica showing the effects on carbohydrate metabolism and differentiation of 3T3-L1 adipocytes. Asia Pac J Clin Nutr . 2007;16(suppl 1):346-352.
21. Judy WV, Hari SP, Stogsdill WW, Judy JS, Naguib YM, Passwater R. Antidiabetic activity of a standardized extract ( Glucosol ) from Lagerstroemia speciosa leaves in Type II
diabetics. A dose-dependence study. J Ethnopharmacol . 2003;87(1):115-117.
22. Fukushima M, Matsuyama F, Ueda N, et al. Effect of corosolic acid on postchallenge plasma glucose levels. Diabetes Res Clin Pract . 2006;73(2):174-777.
23. Garo E, Eldridge GR, Goering MG, et al. Asiatic acid and corosolic acid enhance the susceptibility of Pseudomonas aeruginosa biofilms to tobramycin. Antimicrob Agents Chemother . 2007;51(5):1813-1817.
24. Thuong PT, Min BS, Jin W, et al. Anti-complementary activity of ursane-type triterpenoids from Weigela subsessilis . Biol Pharm Bull . 2006;29(4):830-833.
25. Yamaguchi Y, Yamada K, Yoshikawa N, Nakamura K, Haginaka J, Kunitomo M. Corosolic acid prevents oxidative stress, inflammation and hypertension in SHR/NDmcr-cp rats, a model of metabolic syndrome. Life Sci . 2006;79(26):2474-2479.
26. Kunitomo M. Oxidative stress and atherosclerosis [in Japanese]. Yakugaku Zasshi . 2007;127(12):1997-2014.
27. Na M, Yang S, He L, et al. Inhibition of protein tyrosine phosphatase 1B by ursane-type triterpenes isolated from Symplocos paniculata . Planta Med . 2006;72(3):261-263.
28. Jang DS, Lee GY, Kim J, et al. A new pancreatic lipase inhibitor isolated from the roots of Actinidia arguta . Arch Pharm Res . 2008;31(5):666-670.
29. Yamada K, Hosokawa M, Yamada C, et al. Dietary corosolic acid ameliorates obesity and hepatic steatosis in KK-Ay mice. Biol Pharm Bull . 2008;31(4):651-655.
30. Udell RG, Hari SP, inventors. Corosolic acid formulation and its application for weight loss management and blood sugar balance. US patent 2003-640885. August 14, 2003.
31. Giampapa VC, inventor. Dietary supplement composition and method of use for enhancement of insulin sensitivity. US patent 2006-US20034. May 24, 2006.
32. Matsuyama F, inventor; Jpn Tokkyo Koho. Corosolic acid containing banaba extract for hypoglycemic foods. US patent 2004-126060. April 21, 2004.
33. Hamamoto S, Kogami H, Kohata K, Moriwaki M, Kanada H, Matsuyama F. Single oral dose toxicity of Glucosol in rats. Yakuri to Chiryo . 1999;27(6):1071-1073.
Corosolic acid isolated from the fruit of Crataegus pinnatifida var. psilosa is a protein kinase C inhibitor as well as a cytotoxic agent.
Corosolic acid isolated from the fruit of Cratoegus pinnatifida var. psilosa was tested for anticancer activity. Corosolic acid displayed about the same potent cytotoxic activity as ursolic acid against several human cancer cell lines. In addition, the compound displayed antagonistic activity against the phorbol ester-induced morphological modification of K-562 leukemic cells, indicating the suppression of protein kinase C (PKC) activity by the cytotoxic compound. The compound showed PKC inhibition with dose-dependent pattern in an in vitro PKC assay.
Ahn KS, Hahm MS, Park EJ, Lee HK, Kim IH.. Planta Med. 1998 Jun;64(5):468-70.
Corosolic acid induces apoptosis through mitochondrial pathway and caspases activation in human cervix adenocarcinoma HeLa cells
We investigated the response of human cervix adenocarcinoma HeLa cells to Corosolic acid (CRA) treatment. Our results showed that CRA significantly inhibited cell viability in both a dose- and a time-dependent manner. CRA treatment induced S cell-cycle arrest and caused apoptotic death in HeLa cells. We found that CRA increased in Bax/Bcl-2 ratios by up-regulating Bax expression, disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm. Moreover, CRA treatment triggered the activation of caspase-8, -9 and -3 in HeLa cells. All these results indicate that CRA-induced apoptosis is associated with the activation of caspases via a mitochondrial pathway. Taken together, we believe that CRA could have strong potentials for clinical application in treating human cervix adenocarcinoma and improving cancer chemotherapy.
Xu Yf, Ge Rl, Du J, Xin Hl, Yi Tj, Sheng Jy, Wang Yz, & Ling Cg. Cancer Letters 284 (2009) Pp.229–37