Vernodalol mediates antitumor effects in acute promyelocytic leukemia cells

Wu,Wenjun; Han,Xiaoyan; Wu,Cai; Wei,Guoqing; Zheng,Gaofeng; Li,Yi; Yang,Yang; Yang,Li; He,Donghua; Zhao,Yi; Cai,Zhen

doi:10.3892/ol.2017.7544

Vernodalol mediates antitumor effects in acute promyelocytic leukemia cells

Authors:
- Wenjun Wu
- Xiaoyan Han
- Cai Wu
- Guoqing Wei
- Gaofeng Zheng
- Yi Li
- Yang Yang
- Li Yang
- Donghua He
- Yi Zhao
- Zhen Cai
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Affiliations: Department of Hematology, Bone Marrow Transplantation Center and Multiple Myeloma Treatment Center, The First Affiliated Hospital of Zhejiang Medical College, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, P.R. China
Published online on: December 7, 2017 https://doi.org/10.3892/ol.2017.7544
Pages: 2227-2235
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Acute promyelocytic leukemia (APL) remains a challenge to cure due to the side effects of cytotoxic chemotherapy and drug resistance. The present study demonstrated that vernodalol, an active compound isolated from Centratherum anthelminticum, suppresses APL cell proliferation and induces cell cycle arrest in the G2/M phase through the upregulation of p21 and cell division cycle 25. In addition, vernodalol induced cellular apoptosis via the mitochondrial pathway as observed by the cleavage of caspase‑9 as well as the release of cytochrome c and Smac/DIABLO into the cytosol. A mechanistic study revealed that vernodalol may exert its antitumor activity through the suppression of phosphoinositide 3‑kinase/protein kinase B/mechanistic target of rapamycin signaling. In conclusion, vernodalol may be developed as a potential therapeutic compound for the treatment of APL.

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1	Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR and Sultan C: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 33:451–458. 1976. View Article : Google Scholar : PubMed/NCBI
2	Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A and Bloomfield CD: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 114:937–951. 2009. View Article : Google Scholar : PubMed/NCBI
3	Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P and Degos L: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 76:1704–1709. 1990.PubMed/NCBI
4	Chen Z, Tong JH, Dong S, Zhu J, Wang ZY and Chen SJ: Retinoic acid regulatory pathways, chromosomal translocations and acute promyelocytic leukemia. Genes Chromosomes Cancer. 15:147–156. 1996. View Article : Google Scholar : PubMed/NCBI
5	Jones ME and Saleem A: Acute promyelocytic leukemia. A review of literature. Am J Med. 65:673–677. 1978. View Article : Google Scholar : PubMed/NCBI
6	Cunningham I, Gee TS, Reich LM, Kempin SJ, Naval AN and Clarkson BD: Acute promyelocytic leukemia: Treatment results during a decade at Memorial Hospital. Blood. 73:1116–1122. 1989.PubMed/NCBI
7	Sanz MA, Jarque I, Martin G, Lorenzo I, Martínez J, Rafecas J, Pastor E, Sayas MJ, Sanz G and Gomis F: Acute promyelocytic leukemia. Therapy results and prognostic factors. Cancer. 61:7–13. 1988. View Article : Google Scholar : PubMed/NCBI
8	Fenaux P, Wang ZZ and Degos L: Treatment of acute promyelocytic leukemia by retinoids. Curr Top Microbiol Immunol. 313:101–128. 2007.PubMed/NCBI
9	Kamimura T, Miyamoto T, Harada M and Akashi K: Advances in therapies for acute promyelocytic leukemia. Cancer Sci. 102:1929–1937. 2011. View Article : Google Scholar : PubMed/NCBI
10	Looi CY, Arya A, Cheah FK, Muharram B, Leong KH, Mohamad K, Wong WF, Rai N and Mustafa MR: Induction of apoptosis in human breast cancer cells via caspase pathway byvernodalol isolated from Centratherum anthelminticum (L.) seeds. PLoS One. 8:e566432013. View Article : Google Scholar : PubMed/NCBI
11	Sadagopan SK Ananda, Mohebali N, Looi CY, Hasanpourghadi M, Pandurangan AK, Arya A, Karimian H and Mustafa MR: Forkhead box transcription factor (FOXO3a) mediates the cytotoxic effect ofvernodalol in vitro and inhibits the breast tumor growth in vivo. J Exp Clin Cancer Res. 34:1472015. View Article : Google Scholar : PubMed/NCBI
12	Ashok P, Koti BC, Thippeswamy AH, Tikare VP, Dabadi P and Viswanathaswamy AH: Evaluation of antiinflammatory activity of Centratherum anthelminticum (L) Kuntze seed. Indian J Pharm Sci. 72:697–703. 2010. View Article : Google Scholar : PubMed/NCBI
13	Purnima A, Koti BC, Tikare VP, Viswanathaswamy AH, Thippeswamy AH and Dabadi P: Evaluation of analgesic and antipyretic activities of Centratherum anthelminticum (L) Kuntze seed. Indian J Pharm Sci. 71:461–464. 2009. View Article : Google Scholar : PubMed/NCBI
14	Sharma S and Mehta BK: In vitro antimicrobial efficacy of Centratherum anthelminticum seeds extracts. J Hyg Epidemiol Microbiol Immunol. 35:157–161. 1991.PubMed/NCBI
15	Singhal KC, Sharma S and Mehta BK: Antifilarial activity of Centratherum anthelminticum seed extracts on Setaria cervi. Indian J Exp Biol. 30:546–548. 1992.PubMed/NCBI
16	Arya A, Achoui M, Cheah SC, Abdelwahab SI, Narrima P, Mohan S, Mustafa MR and Mohd MA: Chloroform fraction of Centratherum anthelminticum (L.) seed inhibits tumor necrosis factor alpha and exhibits pleotropic bioactivities: Inhibitory role in human tumor cells. Evid Based Complement Alternat Med. 2012:6272562012. View Article : Google Scholar : PubMed/NCBI
17	Manning BD and Cantley LC: AKT/PKB signaling: Navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI
18	Petrie K, Zelent A and Waxman S: Differentiation therapy of acute myeloid leukemia: Past, present and future. Curr Opin Hematol. 16:84–91. 2009. View Article : Google Scholar : PubMed/NCBI
19	Rabe T, Mullholland D and van Staden J: Isolation and identification of antibacterial compounds from Vernonia colorata leaves. J Ethnopharmacol. 80:91–94. 2002. View Article : Google Scholar : PubMed/NCBI
20	Looi CY, Moharram B, Paydar M, Wong YL, Leong KH, Mohamad K, Arya A, Wong WF and Mustafa MR: Induction of apoptosis in melanoma A375 cells by a chloroform fraction of Centratherum anthelminticum (L.) seeds involves NF-kappaB, p53 and Bcl-2-controlled mitochondrial signaling pathways. BMC Complement Altern Med. 13:1662013. View Article : Google Scholar : PubMed/NCBI
21	Kasim LS, Ferro V, Odukoya OA, Ukpo GE, Seidel V, Gray AI and Waigh R: Cytotoxicity of isolated compounds from the extracts of Struchium sparganophora (Linn) Ktze asteraceae. Pak J Pharm Sci. 24:475–478. 2011.PubMed/NCBI
22	Kupchan SM, Hemingway RJ, Karim A and Werner D: Tumor inhibitors. XLVII. Vernodalol and vernomygdin, two new cytotoxic sesquiterpene lactones from Vernonia amygdalina Del. J Org Chem. 34:3908–3911. 1969. View Article : Google Scholar : PubMed/NCBI
23	Drexler HG: Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia. 12:845–859. 1998. View Article : Google Scholar : PubMed/NCBI
24	Pan MH, Lin CL, Tsai JH, Ho CT and Chen WJ: 3,5,3′,4′, 5′-pentamethoxystilbene (MR-5), a synthetically methoxylated analogue of resveratrol, inhibits growth and induces G1 cell cycle arrest of human breast carcinoma MCF-7 cells. J Agric Food Chem. 58:226–234. 2010. View Article : Google Scholar : PubMed/NCBI
25	Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridandapani S, Anant S and Kuppusamy P: Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther. 6:178–184. 2007. View Article : Google Scholar : PubMed/NCBI
26	Abbas T and Dutta A: p21 in cancer: Intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI
27	Furnari B, Blasina A, Boddy MN, McGowan CH and Russell P: Cdc25 inhibited in vivo and in vitro by checkpoint kinases Cds1 and Chk1. Mol Biol Cell. 10:833–845. 1999. View Article : Google Scholar : PubMed/NCBI
28	Innocente SA, Abrahamson JL, Cogswell JP and Lee JM: p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci USA. 96:pp. 2147–2152. 1999; View Article : Google Scholar : PubMed/NCBI
29	McConkey DJ and Orrenius S: Signal transduction pathways in apoptosis. Stem Cells. 14:619–311. 1996. View Article : Google Scholar : PubMed/NCBI
30	Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP and Wang X: Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science. 275:1129–1132. 1997. View Article : Google Scholar : PubMed/NCBI
31	Martini M, De Santis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signaling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014. View Article : Google Scholar : PubMed/NCBI
32	Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
33	Han S, Zhang G, Li M, Chen D, Wang Y, Ye W and Ji Z: L-securinine induces apoptosis in the human promyelocytic leukemia cell line HL-60 and influences the expression of genes involved in the PI3K/AKT/mTOR signaling pathway. Oncol Rep. 31:2245–2251. 2014. View Article : Google Scholar : PubMed/NCBI
34	Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, Ajani JA and Wu X: Genetic variations in the PI3K/PTEN/AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy. J Clin Oncol. 27:857–871. 2009. View Article : Google Scholar : PubMed/NCBI
35	Ma W, Wang DD, Li L, Feng YK, Gu HM, Zhu GM, Piao JH, Yang Y, Gao X and Zhang PX: Caveolin-1 plays a key role in the oleanolic acid-induced apoptosis of HL-60 cells. Oncol Rep. 32:293–301. 2014. View Article : Google Scholar : PubMed/NCBI
36	Burgering BM and Coffer PJ: Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 376:599–602. 1995. View Article : Google Scholar : PubMed/NCBI
37	Wick MJ, Dong LQ, Riojas RA, Ramos FJ and Liu F: Mechanism of phosphorylation of protein kinase B/Akt by a constitutively active 3-phosphoinositide-dependent protein kinase-1. J Biol Chem. 275:40400–40406. 2000. View Article : Google Scholar : PubMed/NCBI
38	Aoki M, Blazek E and Vogt PK: A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci USA. 98:pp. 136–141. 2001; View Article : Google Scholar : PubMed/NCBI
39	Ali IU, Schriml LM and Dean M: Mutational spectra of PTEN/MMAC1 gene: A tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst. 91:1922–1932. 1999. View Article : Google Scholar : PubMed/NCBI
40	Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, et al: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science. 275:1943–1947. 1997. View Article : Google Scholar : PubMed/NCBI