Table 3.

Preclinical trials of novel agents targeting bone sarcoma stem cells.

Subtype	Agents	Function	Target CSC	Mechanism	Reference
Osteosarcoma	LY294002	PIK3 inhibitor	Sarcosphere	Increase the number of cells in G0/G1 phase and induction of apoptosis via activation of caspase-3, caspase-9, and PARP	[87]
	BRM270	NF-κB inhibitor	CD133	Induce IL-6 mediated apoptosis in osteosarcoma CD133+ cells via downregulation of chromatin SMC2	[91]
	MC1742	HDAC inhibitor	Sarcosphere	Inhibit sphere growth of osteosarcoma and Ewing sarcoma by apoptosis induction with increased acetyl-H3 and acetyl-tubulin levels	[95]
	LNA-133a	miR-133a inhibitor	CD133	Inhibit invasion and metastasis of osteosarcoma CD133+ cells via several target genes including ANXA2	[77]
	Salinomycin	Antibacterial agent	Sarcosphere	Impair Wnt/β-catenin signaling by degradation of β-catenin	[99]
	Ap-SAL-NP	Nanoparticle	CD133	Selectively kill CD133+ cells by salinomycin-loaded PEGylated polynanoparticles conjugated with CD133 aptamer	[89]
	Bufalin	Unknown	Sarcosphere	Induce shrinkage of tumor spheres via activation of caspase-3 and downregulate stem cell markers, targeting miR-148	[100]
Ewing sarcoma	YK-4-209	EWS-FLI1 inhibitor	ALDH	Block RNA helicase A (RHA) binding to EWS-FLI1	[46]
	Enoxacin	Antibacterial agent	CD133	Augment TARBP2 expression, which is repressed in CD133+ Ewing cells, and reduce CD133+ subpopulation through restoration of miRNA expression	[81]
	miR-143,145	Synthetic miRNA	CD133	Repress the expression of target genes Oct3/4, Sox2, as well as EWS-FLI1	[81]