DOI QR코드

DOI QR Code

Aloe vera Inhibits Proliferation of Human Breast and Cervical Cancer Cells and Acts Synergistically with Cisplatin

  • Hussain, Arif (School of Life Sciences, Manipal University) ;
  • Sharma, Chhavi (School of Life Sciences, Manipal University) ;
  • Khan, Saniyah (School of Life Sciences, Manipal University) ;
  • Shah, Kruti (School of Life Sciences, Manipal University) ;
  • Haque, Shafiul (Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University)
  • 발행 : 2015.04.14

초록

Many of the anti-cancer agents currently used have an origin in natural sources including plants. Aloe vera is one such plant being studied extensively for its diverse health benefits, including cancer prevention. In this study, the cytotoxic potential of Aloe vera crude extract (ACE) alone or in combination with cisplatin in human breast (MCF-7) and cervical (HeLa) cancer cells was studied by cell viability assay, nuclear morphological examination and cell cycle analysis. Effects were correlated with modulation of expression of genes involved in cell cycle regulation, apoptosis and drug metabolism by RT-PCR. Exposure of cells to ACE resulted in considerable loss of cell viability in a dose- and time-dependent fashion, which was found to be mediated by through the apoptotic pathway as evidenced by changes in the nuclear morphology and the distribution of cells in the different phases of the cell cycle. Interestingly, ACE did not have any significant cytotoxicity towards normal cells, thus placing it in the category of safe chemopreventive agent. Further, the effects were correlated with the downregulation of cyclin D1, CYP 1A1, CYP 1A2 and increased expression of bax and p21 in MCF-7 and HeLa cells. In addition, low dose combination of ACE and cisplatin showed a combination index less than 1, indicating synergistic growth inhibition compared to the agents applied individually. In conclusion, these results signify that Aloe vera may be an effective anti-neoplastic agent to inhibit cancer cell growth and increase the therapeutic efficacy of conventional drugs like cispolatin. Thus promoting the development of plant-derived therapeutic agents appears warranted for novel cancer treatment strategies.

키워드

참고문헌

  1. Ahmadi A (2012). Potential prevention: Aloe vera mouthwash may reduce radiation-induced oral mucositis in head and neck cancer patients. Chin J Integr Med, 18, 635-40. https://doi.org/10.1007/s11655-012-1183-y
  2. Akev N, Turkay G, Can A, et al (2007). Tumour preventive effect of Aloe vera leaf pulp lectin (Aloctin I) on Ehrlich ascites tumours in mice. Phytother Res, 21, 1070-5. https://doi.org/10.1002/ptr.2215
  3. Alao JP (2007). The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Molecular Cancer, 6, 24.
  4. Alao JP, Lam EW, Ali S, et al (2004). Histone deacetylase inhibitor trichostatin A represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines. Clin Cancer Res, 10, 8094-104. https://doi.org/10.1158/1078-0432.CCR-04-1023
  5. Androutsopoulos VP, Tsatsakis AM, Spandidos DA (2009). BMC Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention. BMC Cancer, 16, 187.
  6. Atul NC, Santhosh CK, Chiranjib B, Subal D (2012). Cytotoxicity study of plant Aloe vera, (Linn). Chronicles Young Scientist, 3, 233-35. https://doi.org/10.4103/2229-5186.99595
  7. Azam S, Hadi N, Khan NU, Hadi SM (2003). Antioxidant and prooxidant properties of caffeine, theobromine and xanthine. Med Sci Monit, 3, 325-30.
  8. Chen YY, Chiang SY, Lin JG, et al (2010). Emodin, aloe-emodin and rhein inhibit migration and invasion in human tongue cancer SCC-4 cells through the inhibition of gene expression of matrix metalloproteinase-9. Int J Oncol, 36, 1113-20.
  9. Chiu TH, Lai WW, Hsia TC, et al (2009). Aloe-emodin induces cell death through S-phase arrest and caspase-dependent pathways in human tongue squamous cancer SCC-4 cells. Anticancer Res, 29, 4503-11.
  10. Choi S, Chung, MH (2003). A review on the relationship between Aloe vera components and their biologic effects. Semin Integr Med, 1, 53-62. https://doi.org/10.1016/S1543-1150(03)00005-X
  11. Chou TH, Liang CH (2009). The molecular effects of aloeemodin (AE)/liposome-AE on human nonmelanoma skin cancer cells and skin permeation. Chem Res Toxicol, 22, 2017-28. https://doi.org/10.1021/tx900318a
  12. Chung YC, Lu LC, Tsai MH, et al (2013). The inhibitory effect of ellagic Acid on cell growth of ovarian carcinoma cells. Evid Based Complement Alternat Med, 2013, 306705.
  13. Cuddeback SM, Yamaguchi H, Komatsu K, et al (2001). Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax. J Biol Chem, 276, 20559-65. https://doi.org/10.1074/jbc.M101527200
  14. Elizabeth A, Musgrove C, Elizabeth Caldon, et al (2011). Cyclin D as a therapeutic target in cancer. Nature Reviews Cancer, 1, 558-72.
  15. Esmat AY, El-Gerzawy SM, Rafaat A (2005). DNA ploidy and S phase fraction of breast and ovarian tumor cells treated with a natural anthracycline analog (aloin). Cancer Biol Ther, 4, 108-12.
  16. Fenig E, Nordenberg J, Beery E, Sulkes J, Wasserman L (2004). Combined effect of aloe-emodin and chemotherapeutic agents on the proliferation of an adherent variant cell line of Merkel cell carcinoma. Oncol Rep, 11, 213-7.
  17. Guo J, Xiao B, Liu Q, Gong Z, Le Y (2008). Suppression of C-myc expression associates with anti-proliferation of aloeemodin on gastric cancer cells. Cancer Invest, 26, 369-74. https://doi.org/10.1080/07357900701788130
  18. Habeeb F, Shakir E, Bradbury F, et al (2007). Screening methods used to determine the anti-microbial properties of Aloe vera inner gel. Methods, 42, 315-320. https://doi.org/10.1016/j.ymeth.2007.03.004
  19. Haddad P, Amouzgar-Hashemi F, Samsami S, Chinichian S, Oghabian MA (2013). Aloe vera for prevention of radiationinduced dermatitis: a self-controlled clinical trial. Curr Oncol, 20, 345-8. https://doi.org/10.3747/co.20.1356
  20. Hamman JH (2008). Composition and applications of Aloe vera leaf gel. Molecules, 3, 1599-616.
  21. Huang PH, Huang CY, Chen MC, et al (2013). Emodin and Aloe-Emodin Suppress Breast Cancer Cell Proliferation through ER $\alpha$ Inhibition. Evid Based Complement Alternat Med, 2013, 376123.
  22. Hussain A, Priyani A, Sadrieh L, Brahmbhatt K, Ahmed M, Sharma C (2012). Concurrent sulforaphane and eugenol induces differential effects on human cervical cancer cells. Integr Cancer Ther, 11, 154-65.
  23. Ismail S, Haris K, Abdul Ghani ARet al (2013). Enhanced induction of cell cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human U87 malignant glioma cells by aloe emodin. J Asian Nat Prod Res, 2013.
  24. Jeena K, Liju VB, Viswanathan R, Kuttan R (2014). Antimutagenic potential and modulation of carcinogenmetabolizing enzymes by ginger essential oil. Phytother Res Phytother Res, 28, 849-55. https://doi.org/10.1002/ptr.5064
  25. Jeon W, Jeon YK, Nam MJ (2012). Apoptosis by aloe-emodin is mediated through down-regulation of calpain-2 and ubiquitin-protein ligase E3A in human hepatoma Huh-7 cells. Cell Biol Int, 36, 163-7. https://doi.org/10.1042/CBI20100723
  26. Joseph B, SJ Raj (2010). Pharmacognostic and phytochemical properties of Aleo vera Linn: An overview. Int J Pharma Sci Rev Res, 4, 106-110.
  27. Kagawa S, Gu J, Swisher SG, et al (2000). Antitumor effect of adenovirus-mediated Bax gene transfer on p53-sensitive and p53-resistant cancer lines. Cancer Res, 60, 1157-61.
  28. Kavitha K, Thiyagarajan P, Rathna Nandhini J, Mishra R, Nagini S (2013). Chemopreventive effects of diverse dietary phytochemicals against DMBA-induced hamster buccal pouch carcinogenesis via the induction of Nrf2-mediated cytoprotective antioxidant, detoxification, and DNA repair enzymes. Biochimie, 95, 1629-39. https://doi.org/10.1016/j.biochi.2013.05.004
  29. Kim IS, Kim Y, Kwak TH, Yoo HH (2013). Effects of $\beta$-lapachone, a new anticancer candidate, on cytochrome P450-mediated drug metabolism. Cancer Chemother Pharmacol, 72, 699-702. https://doi.org/10.1007/s00280-013-2230-x
  30. Kundu JK, Chun KS (2014). The promise of dried fruits in cancer chemoprevention. Asian Pac J Cancer Prev, 15, 3343-52. https://doi.org/10.7314/APJCP.2014.15.8.3343
  31. Kuo PL, Lin TC, Lin CC (2002). The antiproliferative activity of aloe-emodin is through p53-dependent and p21-dependent apoptotic pathway in human hepatoma cell lines. Life Sci, 71, 1879-92. https://doi.org/10.1016/S0024-3205(02)01900-8
  32. Li Q, Zhou S, Jing J, et al (2013). Oligosaccharide from apple induces apoptosis and cell cycle arrest in HT29 human colon cancer cells. Int J Biol Macromol, 57, 245-54. https://doi.org/10.1016/j.ijbiomac.2013.03.034
  33. Lin ML, Lu YC, Chung JG, et al (2010). Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. Cancer Lett, 291, 46-58. https://doi.org/10.1016/j.canlet.2009.09.016
  34. Lissoni P, Rovelli F, Brivio F, et al (2009). A randomized study of chemotherapy versus biochemotherapy with chemotherapy plus Aloe arborescens in patients with metastatic cancer. In vivo, 23, 171-5.
  35. Mijatovic S, Maksimovic-Ivanic D, Radovic J, et al (2005). Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin. Cell Mol Life Sci, 62, 1275-82. https://doi.org/10.1007/s00018-005-5041-3
  36. Nejatzadeh-Barandozi F (2013). Antibacterial activities and antioxidant capacity of Aloe vera. Org Med Chem Lett, 3, 5. https://doi.org/10.1186/2191-2858-3-5
  37. Niciforovic A, Adzic M, Spasic SD, Radojcic MB (2007). Antitumor effects of a natural anthracycline analog (Aloin) involve altered activity of antioxidant enzymes in HeLaS3 cells. Cancer Biol Ther, 6, 1200-5.
  38. Nishimura M, Koeda A, Suganuma Y, et al (2007). Comparison of inducibility of CYP1A and CYP3A mRNAs by prototypical inducers in primary cultures of human, cynomolgus monkey, and rat hepatocytes. Drug Metab Pharmacokinet, 22, 178-86. https://doi.org/10.2133/dmpk.22.178
  39. Oyagbemi AA, Azeez OI, Saba AB (2009). Interactions between reactive oxygen species and cancer: the roles of natural dietary antioxidants and their molecular mechanisms of action. Asian Pac J Cancer Prev, 10, 535-44.
  40. Pan Q, Pan H, Lou H, Xu Y (2013). Inhibition of the angiogenesis and growth of Aloin in human colorectal cancer in vitro and in vivo. Cancer Cell Int, 13, 69. https://doi.org/10.1186/1475-2867-13-69
  41. Sakakura C, Sweeney EA, Shirahama T, et al (1997). Overexpression of bax sensitizes breast cancer MCF-7 cells to cisplatin and etoposide. Surg Today, 27, 676-9. https://doi.org/10.1007/BF02388231
  42. Sasabe E, Zhou X, Li D, et al (2007). The involvement of hypoxia-inducible factor-1alpha in the susceptibility to gamma-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells. Int J Cancer, 120, 268-77. https://doi.org/10.1002/ijc.22294
  43. Scalbert A, Williamson D (2000). Dietary intake and bioavailability of polyphenols. J Nutr, 3, 2073-85.
  44. Shieh DE, Chen YY, Yen MH, Chiang LC, Lin CC (2004). Emodin-induced apoptosis through p53-dependent pathway in human hepatoma cells. Life Sci, 74, 2279-90. https://doi.org/10.1016/j.lfs.2003.09.060
  45. Shimpo K, Chihara T, Beppu H, et al (2003). Inhibition of azoxymethane-induced DNA adduct formation by Aloe arborescens var. natalensis. Asian Pac J Cancer Prev, 4, 247-51.
  46. Stone A, Sutherland RL, Musgrove EA (2012). Inhibitors of cell cycle kinases: recent advances and future prospects as cancer therapeutics. Crit Rev Oncog, 7, 175-98.
  47. Suboj P, Babykutty S, Srinivas P, Gopala S (2012). Aloe emodin induces G2/M cell cycle arrest and apoptosis via activation of caspase-6 in human colon cancer cells. Pharmacology, 89, 91-8. https://doi.org/10.1159/000335659
  48. Tabolacci C1, Rossi S, Lentini A, et al (2013). Aloin enhances cisplatin antineoplastic activity in B16-F10 melanoma cells by transglutaminase-induced differentiation. Amino Acids, 44, 293-300. https://doi.org/10.1007/s00726-011-1166-x
  49. Tang JC, Yang H, Song XY, et al (2009). Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes. Phytother Res, 23, 159-64. https://doi.org/10.1002/ptr.2572
  50. Tatemichi M, Nomura S, Ogura T, et al (1999). Mutagenic activation of environmental carcinogens by microsomes of gastric mucosa with intestinal Metaplasia. Cancer Res, 59, 3893-8.
  51. Thumvijit T, Taya S, Punvittayagul C, Peerapornpisal Y, Wongpoomchai R (2014). Cancer chemopreventive effect of Spirogyra neglecta (Hassall) Kutzing on diethylnitrosamineinduced hepatocarcinogenesis in rats. Asian Pac J Cancer Prev, 15, 1611-6. https://doi.org/10.7314/APJCP.2014.15.4.1611
  52. Tomasin R, Gomes-Marcondes MC (2011). Oral administration of Aloe vera and honey reduces Walker tumour growth by decreasing cell proliferation and increasing apoptosis in tumour tissue. Phytother Res, 25, 619-23. https://doi.org/10.1002/ptr.3293
  53. Wang AG, Kim SU, Lee SH, Kim SK, Seo SB, Yu DY, Lee DS (2005). Histone deacetylase 1 contributes to cell cycle and apoptosis. Biol Pharm Bull, 28, 1966-70. https://doi.org/10.1248/bpb.28.1966
  54. Xiao BX, Guo J (2009). The anti-proliferation and anti-migration dual effects of aloe-emodin on KB cells and its mechanism. Zhonghua Kou Qiang Yi Xue Za Zhi, 44, 50-2.
  55. Yang N, Zhao B, Rasul A, Qin H, Li J, Li X (2013). PIAS1-modulated Smad2/4 complex activation is involved in zinc-induced cancer cell apoptosis. Cell Death Dis, 19, 811.
  56. Zeng R, Zhou ZW, Wu CF, Zhou YL (2008). Reversal effect of aloe emodin liposomes on cisplatin resistance line A549/DDP human lung adenocarcinoma cells. Zhongguo Zhong Yao Za Zhi, 33, 1443-5.

피인용 문헌

  1. Anti-Proliferative Activity and Apoptosis Induction of an Ethanolic Extract of Boesenbergia pandurata (Roxb.) Schlecht. against HeLa and Vero Cell Lines vol.17, pp.1, 2016, https://doi.org/10.7314/APJCP.2016.17.1.183
  2. Effects of Banxia Xiexin Decoction (半夏泻心汤) on cisplatin-induced apoptosis of human A549 lung cancer cells pp.1993-0402, 2017, https://doi.org/10.1007/s11655-017-2922-x