Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Saponins from Rubus parvifolius L. Induce Apoptosis in Human Chronic Myeloid Leukemia Cells through AMPK Activation and STAT3 Inhibition

  • Ge, Yu-Qing (Zhejiang Provincial Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University) ;
  • Xu, Xiao-Feng (Department of Hematology, Hangzhou Red Cross Hospital) ;
  • Yang, Bo (College of Pharmaceutical Science, Zhejiang Chinese Medical University) ;
  • Chen, Zhe (Zhejiang Provincial Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University) ;
  • Cheng, Ru-Bin (College of Pharmaceutical Science, Zhejiang Chinese Medical University)
  • Published : 2014.07.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Saponins are a major active component for the traditional Chinese medicine, Rubus parvifolius L., which has shown clear antitumor activities. However, the specific effects and mechanisms of saponins of Rubus parvifolius L. (SRP) remain unclear with regard to human chronic myeloid leukemia cells. The aim of this study was to investigate inhibition of proliferation and apoptosis induction effects of SRP in K562 cells and further elucidate its regulatory mechanisms. Materials and Methods: K562 cells were treated with different concentrations of SRP and MTT assays were performed to determine cell viability. Apoptosis induction by SRP was determined with FACS and DAPI staining analysis. Western blotting was used to detect expression of apoptosis and survival related genes. Specific inhibitors were added to confirm roles of STAT3 and AMPK pathways in SRP induction of apoptosis. Results: Our results indicated that SRP exhibited obvious inhibitory effects on the growth of K562 cells, and significantly induced apoptosis. Cleavage of pro-apoptotic proteins was dramatically increased after SRP exposure. SRP treatment also increased the activities of AMPK and JNK pathways, and inhibited the phosphorylation expression level of STAT3 in K562 cells. Inhibition of the AMPK pathway blocked the activation of JNK by SRP, indicating that SRP regulated the expression of JNK dependent oon the AMPK pathway. Furthermore, inhibition of the latter significantly conferred resistance to SRP pro-apoptotic activity, suggesting involvement of the AMPK pathway in induction of apoptosis. Pretreatment with a STAT3 inhibitor also augmented SRP induced growth inhibition and cell apoptosis, further confirming roles of the STAT3 pathway after SRP treatment. Conclusions: Our results demonstrated that SRP induce cell apoptosis through AMPK activation and STAT3 inhibition in K562 cells. This suggests the possibility of further developing SRP as an alternative treatment option, or perhaps using it as adjuvant chemotherapeutic agent for chronic myeloid leukemia therapy.

Keywords

References

  1. Acebedo AR, Amor EC, Jacinto SD (2014). Apoptosis-inducing activity of HPLC fraction from Voacanga globosa (Blanco) Merr. on the human colon carcinoma cell. Asian Pac J Cancer Prev, 15, 617-22. https://doi.org/10.7314/APJCP.2014.15.2.617
  2. Asmaa MJ, Al-Jamal HA, Ang CY, et al (2014). Apoptosis induction in MV4-11 and K562 human leukemic cells by Pereskia sacharosa (Cactaceae) leaf crude extract. Asian Pac J Cancer Prev, 15, 475-81. https://doi.org/10.7314/APJCP.2014.15.1.475
  3. Bewry NN, Nair RR, Emmons MF, et al (2008). Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther, 7, 3169-75. https://doi.org/10.1158/1535-7163.MCT-08-0314
  4. Chahardouli B, Zaker F, Mousavi SA, et al (2013). Evaluation of T315I mutation frequency in chronic myeloid leukemia patients after imatinib resistance. Hematology, 18, 158-62. https://doi.org/10.1179/1607845412Y.0000000050
  5. Chen MB, Zhang Y, Wei MX, et al (2013). Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells. Cellular signalling, 25, 1993-2002. https://doi.org/10.1016/j.cellsig.2013.05.026
  6. Colie S, Van Veldhoven PP, Kedjouar B, et al (2009). Disruption of sphingosine 1-phosphate lyase confers resistance to chemotherapy and promotes oncogenesis through Bcl-2/Bcl-xL upregulation. Cancer Res, 69, 9346-53. https://doi.org/10.1158/0008-5472.CAN-09-2198
  7. Corbin AS, Agarwal A, Loriaux M, et al (2011). Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest, 121, 396-409. https://doi.org/10.1172/JCI35721
  8. De Angel RE, Smith SM, Glickman RD, Perkins SN, Hursting SD (2010). Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer. Nutr Cancer, 62, 1074-86. https://doi.org/10.1080/01635581.2010.492092
  9. Deininger MW, Goldman JM, Melo JV (2000). The molecular biology of chronic myeloid leukemia. Blood, 96, 3343-56.
  10. Druker BJ, Guilhot F, O'Brien SG, et al (2006). Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med, 355, 2408-17. https://doi.org/10.1056/NEJMoa062867
  11. Fan GH, Wang ZM, Yang X, et al (2014). Resveratrol inhibits oesophageal adenocarcinoma cell proliferation via AMP-activated protein kinase signaling. Asian Pac J Cancer Prev, 15, 677-82. https://doi.org/10.7314/APJCP.2014.15.2.677
  12. Fujiwara Y, Takaishi K, Nakao J, et al (2013). Corosolic acid enhances the antitumor effects of chemotherapy on epithelial ovarian cancer by inhibiting signal transducer and activator of transcription 3 signaling. Oncol Lett, 6, 1619-23. https://doi.org/10.3892/ol.2013.1591
  13. Gambacorti-Passerini CB, Gunby RH, Piazza R, et al (2003). Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol, 4, 75-85. https://doi.org/10.1016/S1470-2045(03)00979-3
  14. Gao J, Sun CR, Yang JH, et al (2011). Evaluation of the hepatoprotective and antioxidant activities of Rubus parvifolius L. J Zhejiang Univ Sci B, 12, 135-42. https://doi.org/10.1631/jzus.B1000117
  15. Ge Y, Cheng R, Zhou Y, et al (2012). Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E. Mol Cell Biochem, 368, 17-25. https://doi.org/10.1007/s11010-012-1338-3
  16. Gu Y, Chen T, Meng Z, et al (2012). CaMKII gamma, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine. Blood, 120, 4829-39. https://doi.org/10.1182/blood-2012-06-434894
  17. Hanahan D, Weinberg RA (2011). Hallmarks of cancer: the next generation. Cell, 144, 646-74. https://doi.org/10.1016/j.cell.2011.02.013
  18. Huang XJ, Ren W, Li J, Chen LY, Mei ZN (2013). Anti-inflammatory and anticancer activities of ethanol extract of pendulous monkshood root in vitro. Asian Pac J Cancer Prev, 14, 3569-73. https://doi.org/10.7314/APJCP.2013.14.6.3569
  19. Indran IR, Tufo G, Pervaiz S, Brenner C (2011). Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta, 1807, 735-45. https://doi.org/10.1016/j.bbabio.2011.03.010
  20. Ji C, Yang B, Yang YL, et al (2010). Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition. Oncogene, 29, 6557-68. https://doi.org/10.1038/onc.2010.379
  21. Kim I, He YY (2013). Targeting the AMP-activated protein kinase for cancer prevention and therapy. Front Oncol, 3, 175.
  22. Kma L (2013). Roles of plant extracts and constituents in cervical cancer therapy. Asian Pac J Cancer Prev, 14, 3429-36. https://doi.org/10.7314/APJCP.2013.14.6.3429
  23. Li T, Xu WS, Wu GS, et al (2014). Platycodin D induces apoptosis, and inhibits adhesion, migration and invasion in hepG2 hepatocellular carcinoma cells. Asian Pac J Cancer Prev, 15, 1745-49. https://doi.org/10.7314/APJCP.2014.15.4.1745
  24. Ma LD, Zhou M, Wen SH, et al (2010). Effects of STAT3 silencing on fate of chronic myelogenous leukemia K562 cells. Leuk Lymphoma, 51, 1326-36. https://doi.org/10.3109/10428194.2010.483748
  25. Mao X, Yu CR, Li WH, Li WX (2008). Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. Cell Res, 18, 879-88. https://doi.org/10.1038/cr.2008.86
  26. Vakana E, Altman JK, Glaser H, Donato NJ, Platanias LC (2011). Antileukemic effects of AMPK activators on BCR-ABL-expressing cells. Blood, 118, 6399-402. https://doi.org/10.1182/blood-2011-01-332783
  27. Zhang XJ, Xu XF, Gao RL, Xu JF (2014). Rubus parvifolius L. inhibited the growth of leukemia K562 cells in vitro and in vivo. Chin J Integr Med, 20, 36-42. https://doi.org/10.1007/s11655-013-1537-0
  28. Zheng L, Zhang YM, Zhan YZ, Liu CX (2014). Momordica cochinchinensis seed extracts suppress migration and invasion of human breast cancer ZR-75-30 cells via down-regulating MMP-2 and MMP-9. Asian Pac J Cancer Prev, 15, 1105-10. https://doi.org/10.7314/APJCP.2014.15.3.1105

Cited by

  1. Potential targets of energy restriction mimetic agents in cancer cells vol.10, pp.16, 2014, https://doi.org/10.2217/fon.14.191
  2. Rutin mediated targeting of signaling machinery in cancer cells vol.14, pp.1, 2014, https://doi.org/10.1186/s12935-014-0124-6
  3. Cryptotanshinone suppresses the proliferation and induces the apoptosis of pancreatic cancer cells via the STAT3 signaling pathway vol.12, pp.5, 2015, https://doi.org/10.3892/mmr.2015.4379
  4. Parameters Involved in Autophosphorylation in Chronic Myeloid Leukemia: a Systems Biology Approach vol.16, pp.13, 2015, https://doi.org/10.7314/APJCP.2015.16.13.5273
  5. Treatment with cucurbitacin B alone and in combination with gefitinib induces cell cycle inhibition and apoptosis via EGFR and JAK/STAT pathway in human colorectal cancer cell lines vol.35, pp.5, 2016, https://doi.org/10.1177/0960327115595686
  6. AS1041, a Novel Synthesized Derivative of Marine Natural Compound Aspergiolide A, Arrests Cell Cycle, Induces Apoptosis, and Inhibits ERK Activation in K562 Cells vol.15, pp.11, 2017, https://doi.org/10.3390/md15110346
  7. Saponins as adipokines modulator: A possible therapeutic intervention for type 2 diabetes vol.8, pp.7, 2017, https://doi.org/10.4239/wjd.v8.i7.337
  8. Relevance of functional foods in the Mediterranean diet: the role of olive oil, berries and honey in the prevention of cancer and cardiovascular diseases pp.1549-7852, 2018, https://doi.org/10.1080/10408398.2018.1526165
  9. Total Saponins of Rubus Parvifolius L. Exhibited Anti-Leukemia Effect in vivo through STAT3 and eIF4E Signaling Pathways pp.1993-0402, 2018, https://doi.org/10.1007/s11655-018-2563-8