Melatonin induces antiproliferative activity through modulation of apoptoticpathway in H-ras oncogene transformed 5RP7 cells

In the present study, cytotoxic and apoptotic effects of melatonin were investigated on H-ras oncogene transformed rat embryo fibroblast 5RP7 cells. Melatonin inhibited cell growth and induced apoptosis in 5RP7 cells. We showed inhibition of cell proliferation that was time- and dose-dependent in 5RP7 cells for 24 and 48 h. Melatonin was not toxic in NIH/3T3 primary mouse embryonic fibroblast cells at low doses for 24 and 48 h. The IC50 (380 μM) value of melatonin for 48 h was chosen for advanced assays. The percentages of early/late apoptotic cells to which melatonin (IC50: 380 μM) was administered were increased 6.2-fold in 5RP7 cells compared to controls for 48 h. The melatonin treatment resulted in increased caspase-3 activity and reduced the mitochondrial membrane potential in the 5RP7 cells for 48 h. The cell cycle arrest caused by melatonin was observed in G1 and G2 phases in the cell cycle analyses in 5RP7 cells for 48 h. These findings show that melatonin induces cell death and apoptosis in H-ras oncogene transformed 5RP7 cells. Melatonin may be an anticancer agent against H-ras oncogene activated cancer cells.

Melatonin induces antiproliferative activity through modulation of apoptoticpathway in H-ras oncogene transformed 5RP7 cells

In the present study, cytotoxic and apoptotic effects of melatonin were investigated on H-ras oncogene transformed rat embryo fibroblast 5RP7 cells. Melatonin inhibited cell growth and induced apoptosis in 5RP7 cells. We showed inhibition of cell proliferation that was time- and dose-dependent in 5RP7 cells for 24 and 48 h. Melatonin was not toxic in NIH/3T3 primary mouse embryonic fibroblast cells at low doses for 24 and 48 h. The IC50 (380 μM) value of melatonin for 48 h was chosen for advanced assays. The percentages of early/late apoptotic cells to which melatonin (IC50: 380 μM) was administered were increased 6.2-fold in 5RP7 cells compared to controls for 48 h. The melatonin treatment resulted in increased caspase-3 activity and reduced the mitochondrial membrane potential in the 5RP7 cells for 48 h. The cell cycle arrest caused by melatonin was observed in G1 and G2 phases in the cell cycle analyses in 5RP7 cells for 48 h. These findings show that melatonin induces cell death and apoptosis in H-ras oncogene transformed 5RP7 cells. Melatonin may be an anticancer agent against H-ras oncogene activated cancer cells.

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  • Akalın Çiftçi G, Ulusoylar Yıldırım S, Altıntop, MD, Kaplancıklı ZA (2014). Induction of apoptosis in lung adenocarcinoma and glioma cells by some oxadiazole derivatives. Med Chem Res 23: 3353–3362.
  • Altun A, Uğur-Altun B (2007). Melatonin: therapeutic and clinical utilization. J Clin Pract 61: 835–845.
  • Bejarano I, Redondo PC, Espino J, Rosado JA, Paredes SD, Barriga C, Reiter RJ, Pariente JA (2009). Melatonin induces mitochondrial-mediated apoptosis in human myeloid HL-60 cells. J Pineal Res 46: 392–400.
  • Brunner TB, Hahn SM, McKenna WG, Bernhard EJ (2004). Radiation sensitization by inhibition of activated ras. Strahlenther Onkol 180:731–40.
  • Büyükavcı M, Özdemir Ö, Buck S, Stout M, Ravindranath Y, Savaşan S (2006). Melatonin cytotoxicity in human leukemia cells: relation with its pro-oxidant effect. Fundam Clin Pharmacol 20: 73–79.
  • Chottanapund S, Van Duursen MBM, Navasumrit P, Hunsonti P, Timtavorn S, Ruchirawat M, Van den Berg M (2014). Anti- aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts. Toxicol In Vitro 28: 1215–1221.
  • Cos S, Mediavilla MD, Fernandez R, Gonzalez-Lamuno D, Sanchez- Barcelo EJ (2002). Does melatonin induce apoptosis in MCF7 human breast cancer cells in vitro? J Pineal Res 32: 90–96.
  • Cos S, Recio J, Sanchez-Barcelo EJ (1996). Modulation of the length of the cell cycle time of MCF7 human breast cancer cells by melatonin. Life Sci 58: 811–816.
  • Cucina A, Proietti S, D’Anselmi F, Coluccia P, Dinicola S, Frati L, BizzarriM (2009). Evidence for a biphasic apoptotic pathway induced by melatonin in MCF7 breast cancer cells. J Pineal Res 46: 172–180.
  • Espesito E, Lacono A, Muia C, Crisafulli C, Mattace Raso GM, Bramanti P, Meli R, Cuzzocrea S (2008). Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. J Pineal Res 44: 78–87.
  • Fan LL, Sun GP, Wei W, Wang ZG, Ge L, Fu WZ, Wang H (2010). Melatonin and Doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines. World J Gastroenterol 16: 1473–1481.
  • Farriol M, Venereo Y, Orta X, Castellanos JM, Segovia-Silvestre T (2000). In vitro effects of melatonin on cell proliferation in a colon adenocarcinoma line. J Appl Toxicol 20: 21–24.
  • Fischer TW, Zmijewski MA, Wortsman J, Slominski A (2008). Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes. J Pineal Res 44: 397–407.
  • Furuya Y, Yamamoto K, Kohno N, Ku Y, Saito Y (1994). 5-Fluorouracil attenuates an oncostatic effect of melatonin on estrogen-sensitive human breast cancer cells (MCF7). Cancer Lett 81: 95–98.
  • Garcia-Santos G, Antolin I, Herrera F, Martin V, Rodriguez-Blanco J, Carrera MP, Rodriguez C (2006). Melatonin induces apoptosis in human neuroblastoma cancer cells. J Pineal Res 41: 130–135.
  • Hong Y, Won J, Lee Y, Lee S, Park K, Chang KT, Hong Y (2014). Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells. J Pineal Res 56: 264–274.
  • Joo SS, Yoo YM (2009). Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. J Pineal Res 47: 8–14.
  • Jung B, Ahmad N (2006). Melatonin in cancer management: progress and promise. Cancer Res 66: 9789–9793.
  • Kanishi Y, Kobayashi Y, Noda S, Ishizuka B, Saito K (2000). Differential growth inhibitory effect of melatonin o two endometrial cancer cell lines. J Pineal Res 28: 227–233.
  • Leon-Blanco MM, Guerrero JM, Reiter RJ, Calvo JR, Pozo D (2003). Melatonin inhibits telomerase activity in the MCF7 tumor cell line both in vivo and in vitro. J Pineal Res 35: 204–211.
  • Liburdy RP, Sloma TR, Sokolic R, Yaswen P (1993). ELF magnetic fields, breast cancer and melatonin: 60 Hz fields block melatonin’s oncostatic action on ER + breast cancer cell proliferation. J Pineal Res 14: 89–97.
  • Mancini M, Nicholson DW, Roy S (1998) The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. J Cell Biol 140: 1485–1490.
  • Martinez-Campa C, Gonzalez A, Mediavilla MD, Alonso-Gonzalez C, Alvarez-GarciaV, Sanchez-Barcelo EJ, Cos S (2009). Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells. Brit J Cancer 101: 1613–1619.
  • Martin-Renedo J, Mauriz JL, Jorquera F, Ruiz-Andres O, Gonzalez P, Gonzalez-Gallego J (2008). Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res 45: 532–540.
  • Petranka J, Baldwin W, Biermann J, Jayadev S, Barrett JC, Murphy E (1999). The oncostatic action of melatonin in an ovarian carcinoma cell line. J Pineal Res 26: 129–136.
  • Pizarro JG, Yeste-Velasco M, Esparza JL, Verdaguer E, Pallas M, Camins A, Folch J (2008). The antiproliferative activity of melatonin in B65 rat dopaminergic neuroblastoma cells is related to the downregulation of cell cycle-related genes. J Pineal Res 45: 8–16.
  • Plaimee P, Weerapreeyakul N, Barusrux S, Johns NP (2015). Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif 48: 67–77.
  • Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ (2003). Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60: 1407–1426.
  • Sánchez-Hidalgo M, Lee M, Lastra CA, Guerrero JM, Pachham G (2012). Melatonin inhibits cell proliferation and induces caspase activation and apoptosis in human malignant lymphoid cell lines. J Pineal Res 53: 366–373.
  • Uguz AC, Cig B, Espino J, Bejarano I, Naziroglu M, Rodríguez AB, Pariente JA (2012). Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells. J Pineal Res 53: 91–98.
  • Weiwer M, Bittker JA, Lewis TA, Shimada K, Yang WS, MacPherson L, Dandapani S, Palmer M, Stockwell BR, Schreiber SL et al. (2012). Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett 22: 1822–1826.
  • Xu C, Wu A, Zhu H, Fang H, Xu L, Ye J, Shen J (2013). Melatonin is involved in the apoptosis and necrosis of pancreatic cancer cell line SW-1990 via modulating of Bcl-2/Bax balance. Biomed Pharmacother 67: 133–139.
  • Yang QH, Xu JN, Xu RK, Pang SF (2006). Inhibitory effects of melatonin on the growth of pituitary prolactin-secreting tumor in rats. J Pineal Res 40: 230–235.
  • Yürüker V,  Nazıroğlu M,  Şenol N (2015). Reduction in traumatic brain injury-induced oxidative stress, apoptosis, and calcium entry in rat hippocampus by melatonin: possible involvement of TRPM2 channels. Metab Brain Dis 30: 223–231.
Turkish Journal of Biology-Cover
  • ISSN: 1300-0152
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK
Sayıdaki Diğer Makaleler

Melatonin, mitochondria, and Ca2+ homeostasis in the exocrine pancreas: an overview

Antonio GONZALEZ, Patricia SANTOFIMIA-CASTAÃ'O, Gines Maria SALIDO

Expression profiles of genes related to melatonin and oxidative stress in human renal proximal tubule cells treated with antibiotic amphotericin B and its modified forms

Joanna GOLA, Aleksandra SKUBIS, Bartosz SIKORA, Celina KRUSZNIEWSKA-RAJS, Jolanta ADAMSKA, Urszula MAZUREK, Barbara STRZALKA-MROZIK, Grzegorz CZERNEL, Mariusz GAGOS

Melatonin induces antiproliferative activity through modulation of apoptoticpathway in H-ras oncogene transformed 5RP7 cells

Ayşe KAPLAN, Gülşen Akalin ÇİFTÇİ, Hatice Mehtap KUTLU

The effects of topical melatonin on oxidative stress, apoptosis signals,and p53 protein expression during cutaneous wound healing

Azize ŞENER, Özge ÇEVİK, Özge DOĞAN, Nazli Gül ALTINDİŞ, Halil AKSOY, Betül OKUYAN

Prooxidant effects of melatonin: a brief review

Malwina S MUNIK, Cem EKMEKÇİOĞLU

Melatonin is a potent modulator of antioxidative defense and cellular proliferation against aluminum toxicity in rats

Nihal Ömür BULAN, Guner SARIKAYA-UNAL, Sevim TUNALI, Pelin Arda PİRİNÇÇİ, Refiye YANARDAG

Effects of photoperiod variations and alpha-lipoic acid treatment on melatonin,cortisol, and oxidative stress levels in the blood of rats

Cahide ÇEVİK, Recep ASLAN

Melatonin increased vitamin C and antioxidant enzyme values in the plasma,heart, liver, and kidney of Adriamycin-treated rats

Ali Ziya KARAKILÇIK, Muharrem BİTİREN, Mustafa ZERİN, Hakim ÇELİK, Nurten AKSOY

Editorial 'Melatonin and Mitochondria Interact in Diseases'

Jose Antonio Pariente LLANOS, Mustafa NAZİROĞLU

The effects of midazolam and etomidate on the antioxidant system in the rat liver

Dilek BAYRAM, Meral ÖNCÜ, Efkan UZ, Haci Ramazan YILMAZ, Ayşe YİĞİT, Ahmet KOÇAK