Overcoming Therapeutic Resistance of Bone Sarcomas: Overview of the Molecular Mechanisms and Therapeutic Targets for Bone Sarcoma Stem Cells

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 / 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 CD13 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 CD13 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 CD13 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 CD13 Ewing cells, and reduce CD13 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]