Pamidronate, farnesyl transferase, and geranylgeranyl transferase-I inhibitors affects cell proliferation, apoptosis, and OPG/RANKL mRNA expression in stromal cells of giant cell tumor of bone.
Giant cell tumor (GCT) is the most common nonmalignant primary bone tumor reported in Hong Kong. It usually affects young adults between the ages of 20 and 40. This tumor is well known for its potential to recur following treatment. To date no effective adjuvant therapy exists for GCT. Our project aimed to study the effects of pamidronate (PAM), farnesyl transferase inhibitor (FTI-277), geranylgeranyl transferase inhibitor (GGTI-298), and their combinations on GCT stromal cells (SC). Individual treatment with PAM, FTI-277, and GGTI-298, inhibited the cell viability and proliferation of GCT SC in a dose-dependent way. Combination of FTI-277 with GGTI-298 caused synergistic effects in reducing cell viability, and its combination index was 0.49, indicating a strong synergism. Moreover, the combination of FTI-277 with GGTI-298 synergistically enhanced cell apoptosis and activated caspase-3/7, -8, and -9 activities. PAM induced cell-cycle arrest at the S-phase. The combination of PAM with GGTI-298 significantly increased OPG/RANKL mRNA ratio and activated caspase-3/7 activity. Our findings support that the combination of bisphosphonates with GGTIs or FTIs with GGTIs may be used as potential adjuvants in the treatment of GCT of bone.
Lau
Carol P Y
CP
Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Room 74034 5/F, Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong.
Huang
Lin
L
Tsui
Stephen K W
SK
Ng
Patrick K S
PK
Leung
Pui-Yin
PY
Kumta
Shekhar M
SM
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D015870:Gene Expression / Q000187:drug effects; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D053244:Osteoprotegerin / Q000235:genetics*; D000077268:Pamidronate; D054876:Prenylation / Q000187:drug effects; D053245:RANK Ligand / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D001549:Benzamides; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; C096856:FTI 277; C102521:GGTI 298; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D020169:Caspases; D000077268:Pamidronate