Targeting Ameloblatoma into Apoptosis

Ferry Sandra


BACKGROUND: Generally ameloblastoma is a locally aggressive, slow growing, non-metastatic epithelial odontogenic benign tumor. However, rarely some ameloblastoma can metastasize in spite of a benign histologic appearance. Targeting ameloblastoma by inducing it into apoptosis could be a beneficial strategy, since many ameloblastoma cases were reported recurrent after surgical therapy.

CONTENT: To investigate ameloblastoma in cellular aspect,cytological pattern of ameloblastoma was divided intoouter layer/peripheral and inner layer/central cells. Tumor necrosis factor (TNF)-α, Fas ligand (FasL), TNF receptor (TNFR)1/death receptor (DR)1, TNFR2/DR2, DR4, DR5andFas were highly expressed in central than peripheral cells. Despite inducing apoptosis, TNF-α can induce PI3K leading to Akt and p44/42 mitogen-activated protein kinases (MAPK) activation in AM-1 cells, which later induce cell survival and proliferation. Therefore apoptotic induction in ameloblastoma should be suggested in higher TNF-α concentration. Expression of FasL and Fas are closely associated with squamous metaplasia and  granular transformation of the tumor cells, suggesting that apoptosis induced by FasL may play a role in the terminally differentiated or degenerative ameloblastoma cells. TNF-related apoptosis-inducing ligand (TRAIL) has emerged as an apoptotic inducing anticancer agent in tumor cells specifically. TRAIL induced activation of caspases, lowering mitochondrial membrane potential, high number of apoptotic cells in ameloblastoma cells. Therefore, TRAIL could be a potential agent for targeting ameloblastoma, although further study should be explored.

SUMMARY: Targeting ameloblastoma by inducing it into apoptosis could be achieved effectively, although some criteria should be considered. Therefore understanding the underlying apoptosis signaling pathways are necessary for inducing ameloblasotma into apoptosis. Investigations on other apoptosis-related molecules, potential apoptosis-inducing natural products, and novel approach in reprogramming, are important in the future for a better anagement of ameloblastoma.

KEYWORDS: ameloblastoma, apoptosis, TNF, Fas, TRAIL, Akt, MAPK, caspase

Full Text:



Nakamura N, Mitsuyasu T, Higuchi Y, Sandra F, Ohishi M. Growth characteristics of ameloblastoma involving the inferior alveolar nerve: a clinical and histopathologic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001; 91: 557-62, CrossRef.

Sandra F. The proliferative and apoptotic behaviors of ameloblastoma [Dissertation]. Fukuoka: Kyushu University; 2001, dissertation.

Sandra F, Nakamura N, Takeuchi H, Misuyasu T, Shiratsuchi Y, Ohishi M. The Analysis of Apoptosis in Ameloblastoma: Evaluation of Bcl-2, Bcl-X, Bax, Bak. J Dent Indones. 2000; 7: 483-5, article.

Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization Classification of Tumors. Pathology and Genetics of Head and Neck Tumors. Lyon: IARC Press; 2005, book.

Sandra F, Mitsuyasu T, Nakamura N, Shiratsuchi Y, Ohishi M. Immunohistochemical evaluation of PCNA and Ki-67 in ameloblastoma. Oral Oncol. 2001; 37: 193-8, CrossRef.

Sandra F, Nakamura N, Mitsuyasu T, Shiratsuchi Y, Ohishi M. Two relatively distinct patterns of ameloblastoma: an anti-apoptotic proliferating site in the outer layer (periphery) and a pro-apoptotic differentiating site in the inner layer (centre). Histopathology. 2001; 39: 93-8, CrossRef.

Nakamura N, Higuchi Y, Mitsuyasu T, Sandra F, Ohishi M. Comparison of long-term results between different approaches to ameloblastoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002; 93: 13-20, CrossRef.

Sandra F, Nakamura N, Kanematsu T, Hirata M, Ohishi M. The role of MDM2 in the proliferative activity of ameloblastoma. Oral Oncol. 2002; 38: 153-7, CrossRef.

Sandra F. In reply to "Comment on: F. Sandra et al., The role of MDM2 in the proliferative activity of ameloblastoma", Oral Oncology 2002; 38: 153-7. Oral Oncol. 2003; 39: 745, CrossRef.

Sandra F, Harada H, Nakamura N, Ohishi M. Midkine induced growth of ameloblastoma through MAPK and Akt pathways. Oral Oncol. 2004; 40: 274-80, CrossRef.

Hendarmin L, Sandra F, Nakao Y, Ohishi M, Nakamura N. TNFalpha played a role in induction of Akt and MAPK signals in ameloblastoma. Oral Oncol. 2005; 41: 375-82, CrossRef.

Sandra F, Hendarmin L, Nakao Y, Nakamura N, Nakamura S. TRAIL cleaves caspase-8, -9 and -3 of AM-1 cells: a possible pathway for TRAIL to induce apoptosis in ameloblastoma. Tumour Biol. 2005; 26: 258-64, CrossRef.

Hendarmin L, Kawano S, Yoshiga D, Sandra F, Mitsuyasu T, Nakao Y, et al. An anti-apoptotic role of NF-kB in TNFa-induced apoptosis in an ameloblastoma cell line. Oral Sci Int. 2008; 5: 96-103, CrossRef.

Luo HY, Yu SF, Li TJ. Differential expression of apoptosis-related proteins in various cellular components of ameloblastomas. Int J Oral Maxillofac Surg. 2006; 35: 750-5, CrossRef.

Shaikh Z, Niranjan KC. Cell cycle aberration in ameloblastoma and adenomatoid odontogenic tumor: As evidenced by the expression of p53 and survivin. Indian J Dent Res. 2015; 26: 565-70, CrossRef.

Scheper MA, Chaisuparat R, Nikitakis NG, Sauk JJ. Expression and alterations of the PTEN / AKT / mTOR pathway in ameloblastomas. Oral Dis. 2008; 14: 561-8, CrossRef.

Kumamoto H, Ooya K. Immunohistochemical detection of phosphorylated JNK, p38 MAPK, and ERK5 in ameloblastic tumors. J Oral Pathol Med. 2007; 36: 543-9, CrossRef.

Kumamoto H, Ooya K. Detection of mitochondria-mediated apoptosis signaling molecules in ameloblastomas. J Oral Pathol Med. 2005; 34: 565-72, CrossRef.

Khalifa GA, Shokier HM, Abo-Hager EA. Evaluation of neoplastic nature of keratocystic odontogenic tumor versus ameloblastoma. J Egypt Natl Canc Inst. 2010; 22: 61-72, PMID.

Amaral FR, Mateus GC, Bonisson LA, de Andrade BA, Mesquita RA, Horta MC, et al. Cell proliferation and apoptosis in ameloblastomas and keratocystic odontogenic tumors. Braz Dent J. 2012; 23: 91-6, CrossRef.

Sandra F, Matsuki NA, Takeuchi H, Ikebe T, Kanematsu T, Ohishi M, et al. TNF inhibited the apoptosis by activation of Akt serine/threonine kinase in the human head and neck squamous cell carcinoma. Cell Signal. 2002; 14: 771-8, CrossRef.

Sandra F, Hendarmin L, Kukita T, Nakao Y, Nakamura N, Nakamura S. Ameloblastoma induces osteoclastogenesis: a possible role of ameloblastoma in expanding in the bone. Oral Oncol. 2005; 41: 637-44, CrossRef.

Sandra F, Hendarmin L, Nakamura S. Osteoprotegerin (OPG) binds with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL): Suppression of TRAIL-induced apoptosis in ameloblastomas. Oral Oncol. 2006; 42: 415-20, CrossRef.

Sandra F, Hendarmin L, Nakao Y, Nakamura N, Nakamura S. Inhibition of Akt and MAPK pathways elevated potential of TNFalpha in inducing apoptosis in ameloblastoma. Oral Oncol. 2006; 42: 39-45, CrossRef.

Kumamoto H, Ooya K. Expression of survivin and X chromosomelinked inhibitor of apoptosis protein in ameloblastomas. Virchows Arch. 2004; 444: 164-70, CrossRef.

Sandra F, Sidharta MA. Caffeic Acid Induced Apoptosis in MG63 Osteosarcoma Cells Through Activation of Caspases. Mol Cell Biomed Sci. 2017; 1: 28-33, CrossRef.

Arung ET, Wicaksono BD, Handoko YA, Kusuma IW, Shimizu K, Yulia D, et al. Cytotoxic effect of artocarpin on T47D cells. J Nat Med. 2010; 64: 423-9, CrossRef.

Widowati W, Mozef T, Risdian C, Ratnawati H, Tjahjani S, Sandra F. The Comparison of Antioxidative and Proliferation Inhibitor Properties of Piper betle L., Catharanthus roseus [L] G.Don, Dendrophtoe petandra L., Curcuma mangga Val. Extracts on T47D Cancer Cell Line. Int Res J Biochem Bioinform. 2011; 1: 22-8, article.

Arung ET, Kusuma IW, Purwatiningsih S, Roh SS, Yang CH, Jeon S, et al. Antioxidant Activity and Cytotoxicity of the Traditional Indonesian Medicine Tahongai (Kleinhovia hospita L.) Extract. J Acupunct Meridian Stud. 2009; 2: 306-8, CrossRef.

Wicaksono BD, Arung ET, Sandra F. Aktivitas Antikanker dari Kayu Secang. CDK. 2008; 35: 133-7, article.

Widowati W, Maesaroh, Fauziah N, Erawijantari PP, Sandra F. Free Radical Scavenging and Alpha/Beta-glucosidases Inhibitory Activities of Rambutan (Nephelium lappaceum L.) Peel Extract. Indones Biomed J. 2015; 7: 157-62, CrossRef.

Wicaksono BD, Tangkearung E, Sandra F. Brucea javanica leaf extract induced apoptosis in human oral squamous cell carcinoma (HSC2) cells by attenuation of mitochondrial membrane permeability. Indones Biomed J. 2015; 7: 107-10, CrossRef.

Rizal MI, Sandra F. Brucea javanica leaf extract activates caspase-9 and caspase-3 of mitochondrial apoptotic pathway in human oral squamous cell carcinoma. Indones Biomed J. 2016; 8: 43-8, CrossRef.

Arung ET, Wicaksono BD, Handoko A, Kusuma IW, Yulia D, Sandra F. Anti-cancer properties of diethylether extract of wood from sukun (Artocarpus altilis) in human breast cancer (T47D) cells. Trop J Pharm Res. 2009; 8: 317-24, CrossRef.

Wicaksono BD, Handoko A, Arung ET, Kusuma IW, Yulia D, Pancaputra AN, et al. Antiproliferative effect of methanol extract of Piper crocatum Ruiz & Pav leaves on human breast (T47D) cells in-vitro. Trop J Pharm Res. 2009; 8: 345-52, CrossRef.

Arung ET, Wicaksono BD, Sandra F. Prenylated Flavonoid sebagai Senyawa Anti Kanker yang Berpotensi. CDK. 2009; 36: 20-2, article.

Tendean M, Oktaviono YH, Sandra F. Cardiomyocyte Reprogramming: A Potential Strategy for Cardiac Regeneration. Mol Cell Biomed Sci. 2017; 1: 1-5, CrossRef.

Wijaya L, Agustina D, Lizandi AO, Kartawinata MM, Sandra F. Reversing breast cancer stem cell into breast somatic stem cell. Curr Pharm Biotechnol. 2011; 12: 189-95, CrossRef.

Puspitasari RL, Boediono A, Sandra F. Conditioned Medium dari Kultur Primer Sel Syaraf Mus musculus. Prosiding Seminar Biologi. 2013; 10: 1-6, article.

Sandra F, Sudiono J, Sidharta EA, Sunata EP, Sungkono DJ, Dirgantara Y, Chouw A. Conditioned Media of Human Umbilical Cord Blood Mesenchymal Stem Cell-derived Secretome Induced Apoptosis and Inhibited Growth of HeLa Cells. Indones Biomed J. 2014; 6: 57-62, CrossRef.


Indexed by:






The Prodia Education and Research Institute