Inhibitory effects of costunolide and parthenolide from Champi Sirindhorn (Magnolia sirindhorniae) on FLT3 protein expression in EoL-1 leukemic cells

Main Article Content

Sawalee Saosathan
Jalernsri Khounvong
Methee Rungrojsakul
Trinnakorn Katekunlaphan
Singkome Tima
Sawitree Chiampanichayakul
Songyot Anuchapreeda

Abstract

Background: FLT3 (Fms-like tyrosine kinase 3) belongs to the class III receptor tyrosine kinase that is involved in hematopoietic progenitor cell proliferation. It is a prognostic marker for acute myeloblastic leukemia (AML). To date, chemotherapy has been the most frequently used treatment for leukemia. It has had a very good outcome in the early stages of treatment. However, the main problem of chemotherapy is the side effects for leukemia patients, as it may also cause drug resistance after long time treatment. Magnolia (Magnolia spp.) is a medicinal plant and has been used as traditional medicine in China, Japan, and Thailand. It is used for treatment of gastrointestinal disorders, anxiety, allergic disease, etc.


Objectives: Effect of crude fractional extracts and purified active compounds from Magnolia sirindhorniae Noot. & Chalermglin (a new species of Magnoliae spp. which was discovered first in Thailand) were investigated for their cytotoxicity, leukemic cell proliferation, and FLT3 protein suppression in EoL-1 cells. Crude fractional extracts from leaves (fraction No. 1-3), twigs (fraction No. 4-6), and stems (fraction No. 7-9) were fractionated by hexane (fraction No. 1, 4, 7), ethyl acetate (fraction No. 2, 5, 8), methanol (fraction No. 3, 6, 9). The costunolide (1) and parthenolide (2) were purified from n-Hexane fraction from leaves and ethyl acetate fraction from twigs, respectively by column chromatography. Cytotoxicities against leukemic cells were determined by using MTT assay.


Results: Fraction No. 1, 2, 4, 5, 7, 8, costunolide (1), and parthenolide (2) showed strong cytotoxic effects on EoL-1 cells. Furthermore, the non-cytotoxic concentration (20% inhibitory concentration (IC20) values) also decreased FLT3 protein expressions and total cell numbers of EoL-1 cells after treatments. Interestingly, fraction No. 1, 5, costunolide (1), parthenolide (2) decreased the FLT3 protein levels in a time- and dose-dependent manner.


Conclusion: In summary, costunolide and parthenolide are effective compounds from leaves and twigs of M. sirindhorniae to suppress FLT3 protein expression and cell proliferation.

Downloads

Download data is not yet available.

Article Details

How to Cite
Saosathan, S., Khounvong, J., Rungrojsakul, M., Katekunlaphan, T., Tima, S., Chiampanichayakul, S., & Anuchapreeda, S. (2019). Inhibitory effects of costunolide and parthenolide from Champi Sirindhorn (Magnolia sirindhorniae) on FLT3 protein expression in EoL-1 leukemic cells. Journal of Associated Medical Sciences, 53(1), 8-18. Retrieved from https://he01.tci-thaijo.org/index.php/bulletinAMS/article/view/194510
Section
Medical Technology

References

[1]. Choi JH, Ha J, Park JH, Lee JY, Lee YS, Park HJ, et al. Costunolide triggers apoptosis in human leukemia U937 cells by depleting intracellular thiols. Cancer Sci 2002; 93(12): 1327-33.

[2]. Kang JS, Lee KH, Han MH, Lee H, Ahn JM, Han SB, et al. Antiinflammatory activity of methanol extract isolated from stem bark of Magnolia kobus. Phytother Res 2008; 22(7): 883-8.

[3]. Kong C-W, Tsai K, Chin J-H, Chan W-L, Hong C-Y. Magnolol attenuates peroxidative damage and improves survival of rats with sepsis. Shock (Augusta, Ga) 2000; 13(1): 24-8.

[4]. Weeks BS. Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian. Med Sci Monit 2009; 15(11): RA256-RA62.

[5]. Xu Q, Yi L-T, Pan Y, Wang X, Li Y-C, Li J-M, et al. Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents. Prog Neuro-Psychopharmacol Biol Psychiatry 2008; 32(3): 715-25.

[6]. Park E-J, Kim S-y, Zhao Y-Z, Sohn DH. Honokiol reduces oxidative stress, c-jun-NH2-termial kinase phosphorylation and protects against glycochenodeoxycholic acid-induced apoptosis in primary cultured rat hepatocytes. Planta Med 2006; 72(07): 661-4.

[7]. Kobayashi S, Kobayashi H, Matsuno H, Kimura I, Kimura M. Inhibitory effects of anti-rheumatic drugs containing magnosalin, a compound from 'Shin-i' (Flos magnoliae), on the proliferation of synovial cells in rheumatoid arthritis models. Immunopharmacology 1998; 39(2): 139-47.

[8]. Kobayashi S, Kimura I, Kimura M. Inhibitory effect of magnosalin derived from Flos magnoliae on tube formation of rat vascular endothelial cells during the angiogenic process. Biol Pharm Bull 1996; 19(10): 1304-6.

[9]. Kimura M, Kimura I, Guo X, Luo B, Kobayashi S. Combined effects of Japanese‐Sino medicine ‘Kakkon‐to‐ka‐senkyu‐shin'i’and its related combinations and component drugs on adjuvant‐induced inflammation in mice. Phytother Res 1992; 6(4): 209-16.

[10]. Katekunlaphan T, Chalermglin R, Rukachaisirikul T, Chalermglin P. Sesquiterpene lactones from the leaves of Magnolia sirindhorniae. Biochem Syst Ecol 2014; 57: 152-4.

[11]. Rasul A, Bao R, Malhi M, Zhao B, Tsuji I, Li J, et al. Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction. Molecules 2013; 18(2): 1418-33.

[12]. Wang W, Adachi M, Kawamura R, Sakamoto H, Hayashi T, Ishida T, et al. Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity. Apoptosis 2006; 11(12): 2225-35.

[13]. D'anneo A, Carlisi D, Lauricella M, Puleio R, Martinez R, Di Bella S, et al. Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer. Cell Death Dis 2013; 4(10): e891.

[14]. Moon MK, Oh HM, Kwon B-M, Baek N-l, Kim S-H, Kim JS, et al. Farnesyl protein transferase and tumor cell growth inhibitory activities of lipiferolide isolated from Liriodendron tulipifera. Arch Pharmacal Res 2007; 30(3): 299-302.

[15]. Park HJ, Kwon SH, Han YN, Choi JW, Miyamoto K-i, Lee SH, et al. Apoptosis-inducing Costunolide and a novel acyclic monoterpene from the stem bark of Magnolia sieboldii. Arch Pharmacal Res 2001; 24(4): 342-8.

[16]. Choi S-H, Im E, Kang HK, Lee J-H, Kwak H-S, Bae Y-T, et al. Inhibitory effects of costunolide on the telomerase activity in human breast carcinoma cells. Cancer Lett 2005; 227(2): 153-62.

[17]. Rosnet O, Bühring H, Marchetto S, Rappold I, Lavagna C, Sainty D, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 1996; 10(2): 238-48.

[18]. DaSilva N, Hu ZB, Ma W, Rosnet O, Birnbaum D, Drexler HG. Expression of the FLT3 gene in human leukemia-lymphoma cell lines. Leukemia 1994; 8(5): 885-8.

[19]. Zunino SJ, Ducore JM, Storms DH. Parthenolide induces significant apoptosis and production of reactive oxygen species in high-risk pre-B leukemia cells. Cancer Lett 2007; 254(1): 119-27.

[20]. Steele A, Jones D, Ganeshaguru K, Duke V, Yogashangary B, North J, et al. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 2006; 20(6): 1073-9.

[21]. Skalska J, Brookes PS, Nadtochiy SM, Hilchey SP, Jordan CT, Guzman ML, et al. Modulation of cell surface protein free thiols: A potential novel mechanism of action of the sesquiterpene lactone parthenolide. PLoS One 2009; 4(12): e8115.

[22]. Knox GW, Klingeman WE, Paret M, Fulcher A. Management of pests, plant diseases and abiotic disorders of Magnolia species in the Southeastern United States: A review. J Environ Hortic 2012; 30(4): 223-34.

[23]. Nooteboom HP, Chalermglin P. A new species of Magnolia (Magnoliaceae) from Thailand. Blumea 2000; 45(1): 245-7.

[24]. Tachikawa E, Takahashi M, Kashimoto T. Effects of extract and ingredients isolated from Magnolia obovata thunberg on catecholamine secretion from bovine
adrenal chromaffin cells. Biochem Pharmacol 2000; 60(3): 433-40.

[25]. Sangkaruk R, Tima S, Rungrojsakul M, Chiampanichayakul S, Anuchapreeda S. Effects of Saraphi (Mammea siamensis) flower extracts on cell proliferation and Fms-like tyrosine kinase 3 expression in leukemic EoL-1 cell line. Bull Chiang Mai Assoc Med Sci 2016; 49(2): 286-93.

[26]. Tima S, Ichikawa H, Ampasavate C, Okonogi S, Anuchapreeda S. Inhibitory effect of turmeric curcuminoids on FLT3 expression and cell cycle arrest in the FLT3-overexpressing EoL-1 leukemic cell line. J Nat Prod 2014; 77(4): 948-54.