Synergistic Apoptotic Effects of Tocotrienol Isomers and Acalypha wilkesiana on A549 and U87MG Cancer Cells
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Abstract
Recent studies suggested that combined treatment approaches can be used to improve anticancer potency and circumvent the limitations of high-dose tocotrienols administration. Acalypha wilkesiana is a medicinal plant that has been used as an adjunct treatment for cancers in traditional medicine. Herein, the effects of single and combined treatments of ?-, ?- and ?-tocotrienols and ethyl acetate extract (9EA) of Acalypha wilkesiana on lung (A549) and brain (U87MG) cancer cells were investigated. ?- and ?-tocotrienols exhibited higher potent antiproliferative effects against A549 (12.1 ?g/ml and 13.6 ?g/ml) and U87MG cells (3.3 ?g/ml and 5.2 ?g/ml) compared to ?-tocotrienols (9.4 ?g/ml and 92.4 ?g/ml), respectively. Whereas, 9EA induced potent antiproliferative effects against U87MG cells only (2.0 ?g/ml). Combined treatments of tocotrienols and 9EA induced a synergistic growth inhibition with up to 8.4-fold reduction in potent doses of ?-, ?- and ?-tocotrienols on A549 cells. Apoptotic features were also evidenced on A549 cells receiving single and combined treatments. The synergism may greatly improve the therapeutic outcome for lung cancer.
Kajian terbaru mencadangkan bahawa pendekatan gabungan rawatan boleh digunakan untuk meningkatkan potensi antikanser dan menghindari batasan pemberian tocotrienol dos tinggi. Acalypha wilkesiana adalah tumbuhan ubatan yang telah digunakan sebagai rawatan tambahan untuk kanser dalam perubatan tradisional. Di sini, kesan rawatan tunggal dan gabungan ?-, ?- dan ?-tocotrienols dan ekstrak etil asetat (9EA) daripada Acalypha wilkesiana pada paru-paru (A549) dan sel-sel kanser otak (U87MG) telah disiasat. ?- dan ?-tocotrienols menunjukkan kesan antiproliferatif yang lebih tinggi terhadap A549 (12.1 ?g/ml dan 13.6 ?g/ml) dan sel U87MG (3.3 ?g/ml dan 5.2 ?g/ml) berbanding ?-tocotrienols (9.4 ?g/ml), masing-masing. Sedangkan, 9EA merangsang kesan antiproliferatif yang kuat terhadap sel U87MG sahaja (2.0 ?g/ml). Rawatan terapi tocotrienols dan 9EA mencetuskan perencatan pertumbuhan sinergis sehingga pengurangan 8.4 kali ganda dalam dos yang kuat dari ?-, ?- dan ?-tocotrienols pada sel A549. Ciri-ciri apoptotic juga dibuktikan pada sel-sel A549 yang menerima rawatan tunggal dan gabungan. Sinergi ini boleh meningkatkan hasil terapeutik untuk kanser paru-paru.
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References
Abubakar I B, Lim K H and Loh H S. (2014). Alkaloid extracts of Ficus species and palm oil-derived tocotrienols synergistically inhibit proliferation of human cancer cells. Natural Product Research 29: 2137–2140. https://doi.org/10.1080/14786419.2014.991927
Abubakar I B, Lim K -H, Kam T -S and Loh H -S. (2016). Synergistic cytotoxic effects of combined ?-tocotrienol and jerantinine B on human brain and colon cancers. Journal of Ethnopharmacology 184: 107–118. https://doi.org/10.1016/j.jep.2016.03.004
Akl M, Ayoub N and Sylvester P. (2012). Mechanisms mediating the synergistic anticancer effects of combined ?-tocotrienol and sesamin treatment. Planta Medica 78(16): 1731–1739. https://doi.org/10.1055/s-0032-1315302
Büssing A, Stein G M, Herterich-Akinpelu I and Pfüller U. (1999). Apoptosis-associated generation of reactive oxygen intermediates and release of pro-inflammatory cytokines in human lymphocytes and granulocytes by extracts from the seeds of Acalypha wilkesiana. Journal of Ethnopharmacology 66: 301–309. https://doi.org/10.1016/S0378-8741(98)00227-X
Constantinou C, Hyatt J A, Vraka P S, Papas A, Papas K A, Neophytou C, Hadjivassiliou V and Constantinou A I. (2009). Induction of caspase-independent programmed cell death by vitamin E natural homologs and synthetic derivatives. Nutrition and Cancer 61: 864–874. https://doi.org/10.1080/01635580903285130
Constantinou C, Neophytou C M, Vraka P, Hyatt J A, Papas K A and Constantinou A I. (2012). Induction of DNA damage and caspase-independent programmed cell death by vitamin E. Nutrition and Cancer 64: 136–152. https://doi.org/10.1080/01635581.2012.630167
Constantinou C, Papas A and Constantinou A I. (2008). Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs. International Journal of Cancer 752: 739–752. https://doi.org/10.1002/ijc.23689
Elmore S. (2007). Apoptosis: a review of programmed cell death. Toxicologic Pathology 35: 495–516. https://doi.org/10.1080/01926230701320337
Lim S W, Loh H S, Ting K N, Bradshaw T D and Zeenathul N A. (2013). Acalypha wilkesiana ethyl acetate extract enhances the in vitro cytotoxic effects of ? -tocopherol in human brain and lung cancer cells. International Journal of Bioscience Biochemistry and Bioinformatics 3: 335–340.
Lim S W, Loh H S, Ting K N, Bradshaw T D and Zeenathul N A. (2014a). Antiproliferation and induction of caspase-8-dependent mitochondria-mediated apoptosis by ?-tocotrienol in human lung and brain cancer cell lines. Biomedicine and Pharmacotheraphy 68: 1105–1115. https://doi.org/10.1016/j.biopha.2014.10.006
Lim S W, Loh H S, Ting K N, Bradshaw T D and Zeenathul N A. (2014b). Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells. BMC Complementary and Alternative Medicine 14: 469. https://doi.org/10.1186/1472-6882-14-469
Lim S W, Ting K N, Bradshaw T D, Zeenathul N A, Wiart C, Khoo T J, Lim K H and Loh H S. (2011). Acalypha wilkesiana extracts induce apoptosis by causing single strand and double strand DNA breaks. Journal of Ethnopharmacology 138: 616–623. https://doi.org/10.1016/j.jep.2011.10.005
Saraste A and Pulkki K. (2000). Morphologic and biochemical hallmarks of apoptosis. Cardiovascular Research 45: 528–537. https://doi.org/10.1016/S0008-6363(99)00384-3
Shah S, Gapor A and Sylvester P W. (2003). Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. Nutrition and Cancer 45: 236–246. https://doi.org/10.1207/S15327914NC4502_14
Shirode A B and Sylvester P W. (2010). Synergistic anticancer effects of combined g-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkB signaling. Biomedicine and Pharmacotherapy 64: 327–332. https://doi.org/10.1016/j.biopha.2009.09.018
Siegel R, Miller K and Jemal A. (2015). Cancer statistics, 2015. CA. A Cancer Journal for Clinicians. 65: 5–29. https://doi.org/10.3322/caac.21254
Suffness M and Pezzuto J M. (1990). Assays related to cancer drug discovery. In Hostettmann, K. (ed.). Methods in Plant Biochemistry: Assays for Bioactivity. Academic Press, London, 71–133.
Sylvester P W, Kaddoumi A, Nazzal S and El Sayed KA. (2010). The value of tocotrienols in the prevention and treatment of cancer. Journal of the American College of Nutrition 29: 324S–333S. https://doi.org/10.1080/07315724.2010.10719847
Wali V B and Sylvester P W. (2007). Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells. Lipids 42: 1113–1123. https://doi.org/10.1007/s11745-007-3102-0