The effects of Astragalus polysaccharides, tragacanthin, and bassorin on methotrexate-resistant acute lymphoblastic leukemia

Bahareh Samii , Abbas Jafarian , Mohamad Rabbani, Behzad Zolfaghari, Soheila Rahgozar, Elnaz Pouraboutaleb

Abstract


Background and purpose: One strategy to overcome methotrexate (MTX) resistance in acute lymphoblastic leukemia is suppressing MDR1 expression. It has been proved Astragalus polysaccharides (APS) exert their anticancer effect by reversing drug resistance. Due to the structural similarity of tragacanthin and bassorin with APS, we aimed to investigate the effects of the aforementioned polysaccharides on the expression of the MDR1 gene in the MTX-treated CCRF-CEM cells.
Experimental approach: Cytotoxicity of APS, bassorin, and tragacanthin on CCRF-CEM, CCRF-CEM/MTX (cells treated with MTX at IC50), and CCRF-CEM/R cells (CCRF-CEM cells resistant to MTX) was evaluated by MTT assay. The effect of all three compounds on MDR1 expression was evaluated using RT-PCR.
Findings/Results: All the concentrations of tragacanthin, bassorin, and APS (except at 0.8-100 µg/mL in CCRF-CEM) decreased the viability of all the cells compared to the negative control group; and against the positive control (MTX-treated cells), only bassorin at 20-100 µg/mL in CCRF-CEM/R and tragacanthin at 50 and 100 µg/mL in CCRF-CEM/MTX and at 2-100 µg/mL in CCRF-CEM/R decreased cell viability. Tragacanthin diminished MDR1 expression in CCRF-CEM/MTX and CCRF-CEM/R cells, which MTX had already induced.
Conclusion and implication: According to the results of this study, tragacanthin was a potent cytotoxic agent against CCRF-CEM cells and enhanced the chemosensitivity of CCRF-CEM/MTX and CCRF-CEM/R cells to MTX by down-regulation of MDR1 gene expression. Therefore, it could be a promising compound against cancer. Other possible mechanisms of action of tragacanthin should be evaluated and further in vitro and in vivo investigations are required.


Keywords


ALL; APS; Bassorin; MDR1 gene; Tragacanthin.

Full Text:

PDF

References


Aberuyi N, Rahgozar S, Pourabutaleb E, Ghaedi K. Selective dysregulation of ABC transporters in methotrexate-resistant leukemia T-cells can confer cross-resistance to cytarabine, vincristine and dexamethasone, but not doxorubicin. Curr Res Transl Med. 2021;69(1): 103269,1-9.DOI: 10.1016/j.retram.2020.09.003.

Ramezani G, Pourgheysari B, Shirzad H, Sourani Z. Pterostilbene increases Fas expression in T-lymphoblastic leukemia cell lines. Res Pharm Sci. 2019;14(1):55-63.DOI: 10.4103/1735-5362.251853.

Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020;105(11):2524-2539.DOI: 10.3324/haematol.2020.247031.

Su Z, Zhu H, Yuan H, Xu H, Yin J, Liu Y. Multidrug resistance mechanism of acute lymphoblastic leukemia. In: Faderl S. Novel aspects in acute lymphoblastic leukemia. London: INTECH Open Access Publisher; 2011. P: 147-155 DOI: 10.5772/26488.

Rahgozar S, Moafi A, Abedi M, Entezar-e-ghaem M, Moshtaghian J, Ghaedi K, et al. mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. Cancer Biol Ther.2014;15(1):35-41DOI: 10.4161/cbt.26603.

Efferth T, Gillet JP, Sauerbrey A, Zintl F, Bertholet V, de Longueville F, et al. Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia. Mol Cancer Ther. 2006;5(8):1986-1994.DOI: 10.1158/1535-7163.MCT-06-0086.

Mesgari Abbasi M, Valizadeh H, Hamishehkar H, Zakeri-Milani P. Inhibition of P-glycoprotein expression and function by anti-diabetic drugs gliclazide, metformin, and pioglitazone in vitro and in situ. Res Pharm Sci. 2016;11(3):177-186.PMID: 27499787.

Gonen N, Assaraf YG. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012;15(4):183-210.DOI: 10.1016/j.drup.2012.07.002.

Leclerc GJ, Leclerc GM, Kinser T, Barredo JC. Analysis of folylpoly-gamma-glutamate synthetase gene expression in human B-precursor ALL and T-lineage ALL cells. BMC Cancer. 2006;6(1):132,1-12.DOI: 10.1186/1471-2407-6-132.

Jiang B, Yan L, Wu Q. ABCB1 (C1236T) polymorphism affects P-glycoprotein-mediated transport of methotrexate, doxorubicin, actinomycin d, and etoposide. DNA Cell Biol. 2019;38(5):485-490.DOI: 10.1089/dna.2018.4583.

Qin K, Chen K, Zhao W, Zhao X, Luo J, Wang Q, et al. Methotrexate combined with 4-hydroperoxycyclophosphamide downregulates multidrug-resistance P-glycoprotein expression induced by methotrexate in rheumatoid arthritis fibroblast-like synoviocytes via the JAK2/STAT3 pathway. J Immunol Res. 2018;2018:3619320,1-9.DOI: 10.1155/2018/3619320.

Wang L, Wang C, Peng J, Liu Q, Meng Q, Sun H, et al. Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro and in vivo. Toxicol Appl Pharmacol. 2014;277(2):146-154.DOI: 10.1016/j.taap.2014.03.013.

Srivalli KMR, Lakshmi P. Overview of P-glycoprotein inhibitors: a rational outlook. Braz J Pharm Sci. 2012;48(3):353-367.DOI: 10.1590/S1984-82502012000300002.

Najar IA, Sachin BS, Sharma SC, Satti NK, Suri KA, Johri RK. Modulation of P‐glycoprotein ATPase activity by some phytoconstituents. Phytother Res. 2010;24(3):454-458.DOI: 10.1002/ptr.2951.

Bansal T, Jaggi M, Khar R, Talegaonkar S. Emerging significance of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy. J Pharm Pharm Sci. 2009;12(1):46-78.DOI: 10.18433/j3rc77.

Tian QE, De Li H, Yan M, Cai HL, Tan QY, Zhang WY. Effects of Astragalus polysaccharides on P-glycoprotein efflux pump function and protein expression in H22 hepatoma cells in vitro. BMC Complement Altern Med. 2012;12(1):94,1-10.DOI: 10.1186/1472-6882-12-94.

Bratkov VM, Shkondrov AM, Zdraveva PK, Krasteva IN. Flavonoids from the genus Astragalus: phytochemistry and biological activity. Pharmacogn Rev. 2016;10(19):11-32.DOI: 10.4103/0973-7847.176550.

Konkimalla VB, Efferth T. Evidence-based Chinese medicine for cancer therapy. J Ethnopharmacol. 2008;116(2):207-210.DOI: 0.1016/j.jep.2007.12.009.

Jin M, Zhao K, Huang Q, Shang P. Structural features and biological activities of the polysaccharides from Astragalus membranaceus. Int J Biol Macromol. 2014;64:257-266.DOI: 10.1016/j.ijbiomac.2013.12.002.

Bagheri SM, Keyhani L, Heydari M, Dashti-R MH. Antinociceptive activity of Astragalus gummifer gum (gum tragacanth) through the adrenergic system: a in vivo study in mice. J Ayurveda Integr Med. 2015;6(1):19-23.PMID: 25878459.

Farzi M, Yarmand MS, Safari M, Emam-Djomeh Z, Mohammadifar MA. Gum tragacanth dispersions: particle size and rheological properties affected by high-shear homogenization. Int J Biol Macromol. 2015;79:433-439.DOI: 10.1016/j.ijbiomac.2015.04.037.

Ghayempour S, Montazer M, Rad MM. Tragacanth gum as a natural polymeric wall for producing antimicrobial nanocapsules loaded with plant extract. Int J Biol Macromol. 2015;81:514-520.DOI: 10.1016/j.ijbiomac.2015.08.041.

Tian QE, Li HD, Yan M, Cai HL, Tan QY, Zhang WY. Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice. World J Gastroenterol. 2012;18(47):7079-7086.DOI: 10.3748/wjg.v18.i47.7079.

Balaghi S, Mohammadifar MA, Zargaraan A, Gavlighi HA, Mohammadi M. Compositional analysis and rheological characterization of gum tragacanth exudates from six species of Iranian Astragalus. Food Hydrocoll. 2011;25(7):1775-1784.DOI: 10.1016/j.foodhyd.2011.04.003.

Gavlighi HA, Mikkelsen JD, Meyer AS. Tragacanth gum: structural composition, natural functionality and enxymatic conversion as source of potential prebiotic activity. Kgs. Lyngby, Denmark: Technical University of Denmark; 2013. P. 8-17.

Aberuyi N, Rahgozar S, Pourabutaleb E, Ghaedi K. Selective dysregulation of ABC transporters in methotrexate-resistant leukemia T-cells can confer cross-resistance to cytarabine, vincristine and dexamethasone, but not doxorubicin. Curr Res Transl Med. 2021;69(1):103269,1-9.DOI: 10.1016/j.retram.2020.09.003.

Rahimi Babasheikhali S, Rahgozar S, Mohammadi M. Ginger extract has anti-leukemia and anti-drug resistant effects on malignant cells. J Cancer Res Clin Oncol. 2019;145(8):1987-1998. DOI: 10.1007/s00432-019-02949-5.

Commission BP, Council GM, Commission GBM. British pharmacopoeia. Vol 1. London, United Kingdom: Her Majesty's Stationery Office; 2001. P. 3752.

Lawrence JF, Iyengar JR. Gas chromatographic determination of polysaccharide gums in foods after hydrolysis and derivatization. J Chromatogr. 1985;350(1):237-244.DOI: 10.1016/s0021-9673(01)93522-8.

de Beaumais TA, Jacqz-Aigrain E. Intracellular disposition of methotrexate in acute lymphoblastic leukemia in children. Curr Drug Metab. 2012;13(6):822-834.DOI: 10.2174/138920012800840400.

Shu G, Zhao W, Yue L, Su H, Xiang M. Antitumor immunostimulatory activity of polysaccharides from Salvia chinensis Benth. J Ethnopharmacol. 2015;168:237-247.DOI: 10.1016/j.jep.2015.03.065.

Xie X, Wang J, Zhang H. Characterization and antitumor activities of a water-soluble polysaccharide from Ampelopsis megalophylla. Carbohydr Polym. 2015;129:55-61.DOI: 10.1016/j.carbpol.2015.04.037.

Zhou Z, Meng M, Ni H. Chemosensitizing effect of Astragalus polysaccharides on nasopharyngeal carcinoma cells by inducing apoptosis and modulating expression of Bax/Bcl-2 ratio and caspases. Med Sci Monit. 2017;23:462-469.DOI: 10.12659/MSM.903170.

Huang WH, Liao WR, Sun RX. Astragalus polysaccharide induces the apoptosis of human hepatocellular carcinoma cells by decreasing the expression of Notch1. Int J Mol Med. 2016;38(2):551-557.DOI: 10.3892/ijmm.2016.2632.

Wu CY, Ke Y, Zeng YF, Zhang YW, Yu HJ. Anticancer activity of Astragalus polysaccharide in human non-small cell lung cancer cells. Cancer Cell Int. 2017;17:115,1-9.DOI: 10.1186/s12935-017-0487-6.

Cassileth BR, Rizvi N, Deng G, Yeung KS, Vickers A, Guillen S, et al. Safety and pharmacokinetic trial of docetaxel plus an Astragalus-based herbal formula for non-small cell lung cancer patients. Cancer Chemother Pharmacol. 2009;65(1):67-71.DOI: 10.1007/s00280-009-1003-z.

Duan P, Wang Z. Clinical study on effect of Astragalus in efficacy enhancing and toxicity reducing of chemotherapy in patients of malignant tumor. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2002;22(7):515-517.PMID: 12592686.

Zou Y, Liu X. Effect of Astragalus injection combined with chemotherapy on quality of life in patients with advanced non-small cell lung cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2003;23(10):733-735.PMID: 14626183.

Wojtuszkiewicz A, Peters GJ, van Woerden NL, Dubbelman B, Escherich G, Schmiegelow K, et al. Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia. J Hematol Oncol. 2015;8(1):61,1-13.DOI: 10.1186/s13045-015-0158-9.

Sauerbrey A, Zintl F, Volm M. P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia. Br J Cancer. 1994;70(6):1144-1149.DOI: 10.1038/bjc.1994.462.

Dhooge C, De Moerloose B, Laureys G, Kint J, Ferster A, De Bacquer D, et al. P‐glycoprotein is an independent prognostic factor predicting relapse in childhood acute lymphoblastic leukaemia: results of a 6‐year prospective study. Br J Haematol. 1999;105(3):676-683.DOI: 10.1046/j.1365-2141.1999.01378.x.

Gifford AJ, Kavallaris M, Madafiglio J, Matherly LH, Stewart BW, Haber M, et al. P-glycoprotein-mediated methotrexate resistance in CCRF-CEM sublines deficient in methotrexate accumulation due to a point mutation in the reduced folate carrier gene. Int J Cancer. 1998;78(2):176-181. DOI: 10.1002/(sici)1097-0215(19981005)78:2<176:: aid-ijc10>3.0.co;2-9.

Chen Z, Shi T, Zhang L, Zhu P, Deng M, Huang C, et al. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: a review of the past decade. Cancer Lett. 2016;370(1):153-164.DOI: 10.1016/j.canlet.2015.10.010.

Dhooge C, De Moerloose B, Laureys G, Ferster A, De Bacquer D, Philippe J, et al. Expression of the multidrug transporter P-glycoprotein is highly correlated with clinical outcome in childhood acute lymphoblastic leukemia: results of a long-term prospective study. Leuk Lymphoma. 2002;43(2): 309-314.DOI: 10.1080/10428190290006080.

Kanerva J, Tiirikainen MI, Mäkipernaa A, Riikonen P, Möttönen M, Salmi TT, et al. Initial P-glycoprotein expression in childhood acute lymphoblastic leukemia: no evidence of prognostic impact in follow-up. Pediatr Hematol Oncol. 2001;18(1):27-36.DOI: 10.1080/088800101750059837.

Kourti M, Vavatsi N, Gombakis N, Sidi V, Tzimagiorgis G, Papageorgiou T, et al. Expression of multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), lung resistance protein (LRP), and breast cancer resistance protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia. Int J Hematol. 2007;86(2):166-173.DOI: 10.1532/IJH97.E0624.

Szakács G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell. 2004;6(2): 129-137.DOI: 10.1016/j.ccr.2004.06.026.

Kakihara T, Tanaka A, Watanabe A, Yamamoto K, Kanto K, Kataoka S, et al. Expression of multidrug resistance‐related genes does not contribute to risk factors in newly diagnosed childhood acute lymphoblastic leukemia. Pediatr Int. 1999;41(6): 641-647.PMID: 10618884.

Ogretmen B, Barredo JC, Safa AR. Increased expression of lung resistance-related protein and multidrug resistance-associated protein messenger RNA in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2000;22(1):45-49.DOI: 10.1097/00043426-200001000-00009.

Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J, et al. Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer. 1996;65(5):613-619.DOI: 10.1002/(SICI)1097-0215(19960301)65:5<613:: AID-IJC10>3.0.CO;2-8.

Zhang H, Zhang Z, Li G. ABCB1 polymorphism and susceptibility to acute lymphoblastic leukemia: a meta analysis. Int J Clin Exp Med. 2015;8(5): 7585-7591.PMID: 26221303.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.