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Oleanolic acid derivatives induce apoptosis in human leukemia K562 cell involved in inhibition of both Akt1 translocation and pAkt1 expression

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Abstract

Oleanolic acid (OA) derivatives exhibit numerous pleiotropic effects in many cancers. The present study aimed to investigate the molecular mechanisms of 5′-amino-oleana-2,12-dieno[3,2-d]pyrimidin-28-oic acid (compound 4) and oleana-2,12-dieno[2,3-d]isoxazol-28-oic acid (compound 5) inducing apoptosis in human leukemia K562 cell. We investigated the effects of the compounds on K562 cell growth, apoptosis and cell cycle. The compounds showed strong inhibitory effects on K562 cell viability in a dose-dependent manner determined by the 3-(4,5-dimethylthiazoyl)-2,5-diphenyltetrazolium bromide assay and significantly increased chromatin condensation and apoptotic bodies in K562 cells. Flow cytometry assay suggested that the compounds induced inhibition of K562 cell proliferation associated with G1 phase arrest. In addition, the compounds inhibited Akt1 recruiting to membrane in CHO cells which express Akt1-EGFP constitutively and down-regulated the expression of pAkt1 in K562 cell. These results suggested that the compounds can efficiently inhibit proliferation and induce apoptosis perhaps involved in inactivation of Akt1. The OA derivatives may be potential chemotherapeutic agents for the treatment of human cancer.

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Abbreviations

OA:

Oleanolic acid

DMSO:

Dimethyl sulphoxide

FBS:

Fetal bovine serum

PI:

Propidium Iodide

MTT:

3-(4,5-dimethylthiazoyl)-2,5-diphenyltetrazolium bromide

PMSF:

Phenylmethanesulfonyl fluoride

PVDF:

Polyvinylidene fluoride

References

  • Alvarez S, Drane P, Meiller A, Bras M, Deguin-Chambon V, Bouvard V, May E (2006) A comprehensive study of p53 transcriptional activity in thymus and spleen of gamma irradiated mouse: high sensitivity of genes involved in the two main apoptotic pathways. Int J Radiat Biol 82:761–770

    Article  CAS  Google Scholar 

  • Arul D, Subramanian P (2013) Naringenin (citrus flavonone) induces growth inhibition. Cell cycle arrest and apoptosis in human hepatocellular carcinoma cells, Pathol Oncol Res 19:763–770

    Google Scholar 

  • Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276:9817–9824

    Article  CAS  Google Scholar 

  • Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF (2008) The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 8:187–198

    Article  CAS  Google Scholar 

  • Chadalapaka G, Jutooru I, McAlees A, Stefanac T, Safe S (2008) Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives. Bioorg Med Chem Lett 18:2633–2639

    Article  CAS  Google Scholar 

  • Chen L, Zhang Y, Kong X, Peng S, Tian J (2007) Synthesis and biological evaluation of nitric oxide-releasing derivatives of oleanolic acid as inhibitors of HepG2 cell apoptosis. Bioorg Med Chem Lett 17:2979–2982

    Article  CAS  Google Scholar 

  • Cheng S, Eliaz I, Lin J, Sliva D (2013) Triterpenes from Poria cocos suppress growth and invasiveness of pancreatic cancer cells through the downregulation of MMP-7. Int J Oncol 42:1869–1874

    CAS  Google Scholar 

  • Chintharlapalli S, Papineni S, Jutooru I, McAlees A, Safe S (2007) Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor gamma agonists in colon cancer cells. Mol Cancer Ther 6:1588–1598

    Article  CAS  Google Scholar 

  • Chuang JY, Tsai YY, Chen SC, Hsieh TJ, Chung JG (2005) Induction of G0/G1 arrest and apoptosis by 3-hydroxycinnamic acid in human cervix epithelial carcinoma (HeLa) cells. In Vivo 19:683–688

    CAS  Google Scholar 

  • Deeb D, Gao X, Liu Y, Kim SH, Pindolia KR, Arbab AS, Gautam SC (2012) Inhibition of cell proliferation and induction of apoptosis by oleanane triterpenoid (CDDO-Me) in pancreatic cancer cells is associated with the suppression of hTERT gene expression and its telomerase activity. Biochem Biophys Res Commun 422:561–567

    Article  CAS  Google Scholar 

  • Dong LQ, Liu F (2005) PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle. Am J Physiol Endocrinol Metab 289:187–196

    Article  Google Scholar 

  • Gao X, Liu Y, Deeb D, Arbab AS, Guo AM, Dulchavsky SA, Gautam SC (2011) Synthetic oleanane triterpenoid, CDDO-Me, induces apoptosis in ovarian cancer cells by inhibiting prosurvival AKT/NF-kappaB/mTOR signaling. Anticancer Res 31:3673–3681

    CAS  Google Scholar 

  • Gao Z, Hu J, Kang X, Xu C, Ju Y (2012a) Synthesis of A-ring functional derivatives of 18β-glycyrrhetinic acid and their antiproliferative effect in tumor cells. Chem J Chin Univ 33:750–754

    CAS  Google Scholar 

  • Gao Z, Kang X, Hu J, Ju Y, Xu C (2012b) Induction of apoptosis with mitochondrial membrane depolarization by a glycyrrhetinic acid derivative in human leukemia K562 cells. Cytotechnology 64:421–428

    Article  CAS  Google Scholar 

  • Gershtein ES, Scherbakov AM, Shatskaya VA, Kushlinsky NE, Krasil’nikov MA (2007) Phosphatidylinositol 3-kinase/AKT signalling pathway components in human breast cancer: clinicopathological correlations. Anticancer Res 27:1777–1782

    CAS  Google Scholar 

  • Ghayad SE, Cohen PA (2010) Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. Recent Pat Anticancer Drug Discov 5:29–57

    Article  CAS  Google Scholar 

  • Han LT, Li J, Huang F, Yu SG, Fang NB (2009) Triterpenoid saponins from Anemone flaccida induce apoptosis activity in HeLa cells. J Asian Nat Prod Res 11:122–127

    Article  CAS  Google Scholar 

  • Huang H, Tindall DJ (2007) Dynamic FoxO transcription factors. J Cell Sci 120:2479–2487

    Article  CAS  Google Scholar 

  • Huang MT, Ho CT, Wang ZY, Ferraro T, Lou YR, Stauber K, Ma W, Georgiadis C, Laskin JD, Conney AH (1994) Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res 54:701–708

    CAS  Google Scholar 

  • Kang X, Hu J, Gao Z, Ju Y (2012) Synthesis, anti-proliferative and proapoptotic activity of novel oleanolic acid azaheterocyclic derivatives. Med Chem Comm 3:1245–1249

    Google Scholar 

  • Liang C, Ding Y, Song SB, Kim JA, Cuong NM, Ma JY, Kim YH (2013) Oleanane-triterpenoids from Panax stipuleanatus inhibit NF-κB. J Ginseng Res 37:74–79

    Google Scholar 

  • Liu L, Fu J, Li T, Cui R, Ling J, Yu X, Ji H, Zhang Y (2012) NG, a novel PABA/NO-based oleanolic acid derivative, induces human hepatoma cell apoptosis via a ROS/MAPK-dependent mitochondrial pathway. Eur J Pharmacol 691:61–68

    Article  CAS  Google Scholar 

  • Lundholt BK, Linde V, Loechel F, Pedersen HC, Moller S, Praestegaard M, Mikkelsen I, Scudder K, Bjorn SP, Heide M et al (2005) Identification of Akt pathway inhibitors using redistribution screening on the FLIPR and the IN Cell 3000 analyzer. J Biomol Screen 10:20–29

    Article  CAS  Google Scholar 

  • Mahajan K, Mahajan NP (2012) PI3 K-independent AKT activation in cancers: a treasure trove for novel therapeutics. J Cell Physiol 227:3178–3184

    Article  CAS  Google Scholar 

  • Marone R, Cmiljanovic V, Giese B, Wymann MP (2008) Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 1784:159–185

    Article  CAS  Google Scholar 

  • Rao YK, Wu AT, Geethangili M, Huang MT, Chao WJ, Wu CH, Deng WP, Yeh CT, Tzeng YM (2011) Identification of antrocin from Antrodia camphorata as a selective and novel class of small molecule inhibitor of Akt/mTOR signaling in metastatic breast cancer MDA-MB-231 cells. Chem Res Toxicol 24:238–245

    Article  CAS  Google Scholar 

  • Renner O, Blanco-Aparicio C, Carnero A (2008) Genetic modelling of the PTEN/AKT pathway in cancer research. Clin Transl Oncol 10:618–627

    Article  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307:1098–1101

    Article  CAS  Google Scholar 

  • Shyu MH, Kao TC, Yen GC (2010) Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. J Agric Food Chem 58:6110–6118

    Article  CAS  Google Scholar 

  • Tanaka R, Minami T, Tsujimoto K, Matsunaga S, Tokuda H, Nishino H, Terada Y, Yoshitake A (2001) Cancer chemopreventive agents, serratane-type triterpenoids from Picea jezoensis. Cancer Lett 172:119–126

    Article  CAS  Google Scholar 

  • Yan YY, Bai JP, Xie Y, Yu JZ, Ma CG (2013) The triterpenoid pristimerin induces U87 glioma cell apoptosis through reactive oxygen species-mediated mitochondrial dysfunction. Oncol Lett 5:242–248

    CAS  Google Scholar 

  • Yang H, Chen D, Cui QC, Yuan X, Dou QP (2006) Celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res 66:4758–4765

    Article  CAS  Google Scholar 

  • Zeng GZ, Fan JT, Xu JJ, Li Y, Tan NH (2013) Apoptosis induction and G2/M arrest of 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone from Rubia yunnanensis in human cervical cancer Hela cells. Pharmazie 68:293–299

    CAS  Google Scholar 

  • Zhang P, Li H, Chen D, Ni J, Kang Y, Wang S (2007) Oleanolic acid induces apoptosis in human leukemia cells through caspase activation and poly(ADP-ribose) polymerase cleavage. Acta Biochim Biophys Sin (Shanghai) 39:803–809

    Article  CAS  Google Scholar 

  • Zheng QF, Sun HX, He QJ, Ye YP (2006) Induction of apoptosis in HeLa cells by 3beta-hydroxyurs-12-en-27-oic acid. Chem Biodivers 3:742–753

    Article  CAS  Google Scholar 

  • Zhou W, Fu XQ, Liu J, Yu HG (2012) RNAi knockdown of the Akt1 gene increases the chemosensitivity of gastric cancer cells to cisplatin both in vitro and in vivo. Regul Pept 176:13–21

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported in part by International Cooperation Project (5-16), Zhejiang Provincial NSF (Y4110320), NSFC (Nos. 20972086, 21172130), and Opening Foundation of Zhejiang Biomedicine Engineering Key Discipline.

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Authors and Affiliations

  1. College of Life Science, Zhejiang Sci-Tech University, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang Province, China

    Shuhua Pan, Tingting Zheng, Xinyuan Liu & Chuanlian Xu

  2. Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Tsinghua University, Haidian District, Beijing, 100084, China

    Jun Hu & Yong Ju

  3. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Xinyuan Liu

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  1. Shuhua Pan
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  2. Jun Hu
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  3. Tingting Zheng
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  4. Xinyuan Liu
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  5. Yong Ju
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  6. Chuanlian Xu
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Correspondence to Chuanlian Xu.

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Pan, S., Hu, J., Zheng, T. et al. Oleanolic acid derivatives induce apoptosis in human leukemia K562 cell involved in inhibition of both Akt1 translocation and pAkt1 expression. Cytotechnology 67, 821–829 (2015). https://doi.org/10.1007/s10616-014-9722-3

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