JKA97, a Novel Benzylidene Analog of Harmine, Exerts Anti-cancer Effects by Inducing G1 Arrest, Apoptosis, and P53-independent Up-regulation of P21

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 May 5

PMID 22558087

Citations 15

Authors

Xinyi Yang

Wei Wang

Jiang-Jiang Qin

Ming-Hai Wang

Horrick Sharma

John K Buolamwini

Hui Wang

Ruiwen Zhang

Affiliations

Soon will be listed here.

Abstract

JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.

Citing Articles

Anti-tumor potential of Harmine and its derivatives: recent trends and advancements.

Joshi H, Bhushan S, Dimri T, Sharma D, Sak K, Chauhan A Discov Oncol. 2025; 16(1):189.

PMID: 39954215 PMC: 11829886. DOI: 10.1007/s12672-025-01893-w.

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets.

Qin R, You F, Zhao Q, Xie X, Peng C, Zhan G J Hematol Oncol. 2022; 15(1):133.

PMID: 36104717 PMC: 9471064. DOI: 10.1186/s13045-022-01350-z.

Harmine Hydrochloride Mediates the Induction of G2/M Cell Cycle Arrest in Breast Cancer Cells by Regulating the MAPKs and AKT/FOXO3a Signaling Pathways.

Ock C, Kim G Molecules. 2021; 26(21).

PMID: 34771123 PMC: 8588485. DOI: 10.3390/molecules26216714.

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells.

Wang M, Wu X, Yu L, Hu Z, Li X, Meng X Front Oncol. 2021; 11:658608.

PMID: 33937072 PMC: 8085419. DOI: 10.3389/fonc.2021.658608.

A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells.

Yang K, Lee M, Jones P, Liu S, Zhou A, Xu J Sci Adv. 2020; 6(47).

PMID: 33208361 PMC: 7673808. DOI: 10.1126/sciadv.abc3207.

References

Wang W, Rayburn E, Velu S, Chen D, Nadkarni D, Murugesan S . A novel synthetic iminoquinone, BA-TPQ, as an anti-breast cancer agent: in vitro and in vivo activity and mechanisms of action. Breast Cancer Res Treat. 2009; 123(2):321-31. PMC: 3769174. DOI: 10.1007/s10549-009-0638-0. View

Janssen A, Medema R . Mitosis as an anti-cancer target. Oncogene. 2011; 30(25):2799-809. DOI: 10.1038/onc.2011.30. View

Ishida J, Wang H, Bastow K, Hu C, Lee K . Antitumor agents 201. Cytotoxicity of harmine and beta-carboline analogs. Bioorg Med Chem Lett. 1999; 9(23):3319-24. DOI: 10.1016/s0960-894x(99)00598-3. View

El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J . WAF1, a potential mediator of p53 tumor suppression. Cell. 1993; 75(4):817-25. DOI: 10.1016/0092-8674(93)90500-p. View

Wang W, Rayburn E, Zhao Y, Wang H, Zhang R . Novel ginsenosides 25-OH-PPD and 25-OCH3-PPD as experimental therapy for pancreatic cancer: anticancer activity and mechanisms of action. Cancer Lett. 2009; 278(2):241-248. PMC: 2693424. DOI: 10.1016/j.canlet.2009.01.005. View

Koehn F, Carter G . The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005; 4(3):206-20. DOI: 10.1038/nrd1657. View

Song Y, Kesuma D, Wang J, Deng Y, Duan J, Wang J . Specific inhibition of cyclin-dependent kinases and cell proliferation by harmine. Biochem Biophys Res Commun. 2004; 317(1):128-32. DOI: 10.1016/j.bbrc.2004.03.019. View

Luo W, Liu J, Li J, Zhang D, Liu M, Addo J . Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent and p53-independent pathway. J Biol Chem. 2008; 283(13):8624-33. PMC: 2417161. DOI: 10.1074/jbc.M707860200. View

Wang W, Wang H, Rayburn E, Zhao Y, Hill D, Zhang R . 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol, a novel natural product for prostate cancer therapy: activity in vitro and in vivo and mechanisms of action. Br J Cancer. 2008; 98(4):792-802. PMC: 2259179. DOI: 10.1038/sj.bjc.6604227. View

10.

Wang W, Rayburn E, Hang J, Zhao Y, Wang H, Zhang R . Anti-lung cancer effects of novel ginsenoside 25-OCH(3)-PPD. Lung Cancer. 2009; 65(3):306-11. PMC: 2748063. DOI: 10.1016/j.lungcan.2008.11.016. View

11.

Wang W, Zhao Y, Rayburn E, Hill D, Wang H, Zhang R . In vitro anti-cancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng. Cancer Chemother Pharmacol. 2006; 59(5):589-601. DOI: 10.1007/s00280-006-0300-z. View

12.

Zhang Z, Wang H, Li M, Agrawal S, Chen X, Zhang R . MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem. 2004; 279(16):16000-6. DOI: 10.1074/jbc.M312264200. View

13.

Wang W, Rayburn E, Velu S, Nadkarni D, Murugesan S, Zhang R . In vitro and in vivo anticancer activity of novel synthetic makaluvamine analogues. Clin Cancer Res. 2009; 15(10):3511-8. PMC: 3769181. DOI: 10.1158/1078-0432.CCR-08-2689. View

14.

Mishra B, Tiwari V . Natural products: an evolving role in future drug discovery. Eur J Med Chem. 2011; 46(10):4769-807. DOI: 10.1016/j.ejmech.2011.07.057. View

15.

Kang K, Kim W, Choi K . p21 promotes ceramide-induced apoptosis and antagonizes the antideath effect of Bcl-2 in human hepatocarcinoma cells. Exp Cell Res. 1999; 253(2):403-12. DOI: 10.1006/excr.1999.4644. View

16.

Nathanson K, Domchek S . Therapeutic approaches for women predisposed to breast cancer. Annu Rev Med. 2010; 62:295-306. DOI: 10.1146/annurev-med-010910-110221. View

17.

Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90. DOI: 10.3322/caac.20107. View

18.

Oakman C, Santarpia L, Di Leo A . Breast cancer assessment tools and optimizing adjuvant therapy. Nat Rev Clin Oncol. 2010; 7(12):725-32. DOI: 10.1038/nrclinonc.2010.170. View

19.

LaBaer J, Garrett M, Stevenson L, Slingerland J, Sandhu C, Chou H . New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997; 11(7):847-62. DOI: 10.1101/gad.11.7.847. View

20.

Eskelinen M, Hippelainen M, Kettunen J, Salmela E, Penttila I, Alhava E . Clinical value of serum tumour markers TPA, TPS, TAG 12, CA 15-3 and MCA in breast cancer diagnosis; results from a prospective study. Anticancer Res. 1994; 14(2B):699-703. View