Molecular mechanisms of chemoresistance in osteosarcoma (Review)

Abstract

Due to the emergence of adjuvant and neoadjuvant chemotherapy, the survival rate has been greatly improved in osteosarcoma (OS) patients with localized disease. However, this survival rate has remained unchanged over the past 30 years, and the long-term survival rate for OS patients with metastatic or recurrent disease remains poor. To a certain extent, the reason behind this may be ascribed to the chemoresistance to anti-OS therapy. Chemoresistance in OS appears to be mediated by numerous mechanisms, which include decreased intracellular drug accumulation, drug inactivation, enhanced DNA repair, perturbations in signal transduction pathways, apoptosis- and autophagy-related chemoresistance, microRNA (miRNA) dysregulation and cancer stem cell (CSC)-mediated drug resistance. In addition, methods employed to circumvent these resistance mechanism have been shown to be effective in the treatment of OS. However, almost all the current studies on the mechanisms of chemoresistance in OS are in their infancy. Further studies are required to focus on the following aspects: i) Improving the delivery of efficacy through novel delivery patterns; ii) improving the understanding of the signal transduction pathways that regulate the proliferation and growth of OS cells; iii) elucidating the signaling pathways of autophagy and its association with apoptosis in OS cells; iv) utilizing high-throughput miRNA expression analysis to identify miRNAs associated with chemoresistance in OS; and v) identifying the role that CSCs play in tumor metastasis and in-depth study of the mechanism of chemoresistance in the CSCs of OS.

Keywords: chemoresistance; osteosarcoma.

Figure 1

Mechanisms of chemoresistance in OS. 1, Decreased intracellular drug accumulation mediated by lower RFC. 2, Increased efflux of drugs through P-GP. 3, Drug inactivation by GSTP1. 4, Enhanced DNA repair by APE1 or ERCC. 5, miRNA dysregulation. OS, osteosarcoma; RFC, reduced folate carrier; P-GP, P-glycoprotein; GSTP1, glutathione S-transferase P1; APE1, apurinic endonuclease 1; ERCC, excision repair cross-complementing; miRNA, microRNAs.

Figure 2

Mechanisms of chemoresistance in OS. 1 and 2, Perturbations in mTOR or IGF-IR signal transduction pathways. 3 and 4, Apoptosis and autophagy-related chemoresistance. 3-MA, 3-methyladenine; AKT (PKB), protein kinase B; Bad, basal cell lymphoma 2-associated death protein; Bak, basal cell lymphoma 2 homologous antagonist killer protein; Bax, basal cell lymphoma 2-associated X protein; Bcl-2, basal cell lymphoma 2 protein; Bcl-xl, basal cell lymphoma extra large protein; ERK, extracellular signal-regulated kinase; FIP200, family interacting protein of 200 kDa; HMGB1, high mobility group box 1 protein; IGF-I, insulin-like growth factor I; IGF-IR, IGF-I receptor; MAPK, mitogen activated protein kinase; mAtg13, mammalian autophagy-related gene 13; Mdm2, murine double minute 2; mTOR, mammalian target of rapamycin; OS, osteosarcoma; p70S6K, ribosomal protein S6 kinases, 70 kDa; PI3K, phosphoinositide 3-kinase; PI3KCIII, PI3K class III; ULK1, Unc-51-like kinase 1.