Surmounting Chemotherapy and Radioresistance in Chondrosarcoma: Molecular Mechanisms and Therapeutic Targets

Table 1

A summary of the mechanisms involved in chemotherapy and radiation resistance in chondrosarcoma cells. Summarized here are the various molecular mechanisms responsible chemotherapy and radiation resistance in chondrosarcoma, strategies to overcome these mechanisms, and the results of studies testing these strategies as possible adjuvants to traditional surgical treatments. See text for more in-depth discussions of each topic.

Resistance mechanism	Effect within the cell	Therapeutic strategies	Has treatment been tested?
P-glycoprotein expression	Exports chemotherapy drugs from within the cell	Gene silencing using siRNA pharmacologic inhibition using C-4	In vitro: dramatic increases in chemosensitivity
Telomerase activity	“Immortal” cell phenotype	BIBR1532- pharmacological telomerase inhibitor	BIBR152- in vitro: slowed growth and increased sensitivity to cisplatin.
		GRN 163L- pharmacological telomerase inhibitor	GRN 163L- in vivo: but not in chondrosarcoma—helpful addition in leukemia treatment
Angiogenesis	Supports larger tumors, allows metastasis	SU6668-inhibits receptors for VEGF, FGF, PDGF ET-743 and plasminogen-related protein B-chemotherapeutic and endothelial-cell-metabolism downregulator	In vivo murine model: decreased tumor size, vascularization.
			In vivo murine model:induction of profound necrosis, inhibition of neovascularization
COX-2 expression	Unclear, but associated with poor prognosis	COX-2 inhibitors-mechanism of action remains unclear	In vivo: slows cancer growth, although growth relapses after six weeks of treatment
Melovonate synthesis	Shift bone remodeling balance toward resorption	Bisphosphonates-inhibit melovonate synthesis in the bone microenvironment	In vivo: induction of apoptosis, inhibition of metalloproteinase activity, and reduction of VEGF levels
Tumor Suppressor p16 Mutation	Decreased tendency toward apoptosis	p16-restoring virusOncolytic viruses-selectively target immune-inducing molecules to cells with pathway defects	In vitro: increased radiosensitivity in p16-deficient cells.
			In vivo, but not in chondrosarcoma-results show strong selectivity, desired efficacy, no serious side effects.
Increased expression of Bcl-2, Bcl-xL, and XIAP	Decreased tendency toward apoptosis	Downregulation via pharmacotherapy/siRNA-shift cellular balance toward apoptosis	In vitro: increased radiosensitivity
			In vivo: increased chemosensitivity
Hypoxia	Decreased ROS creation by radiation	Acridine orange-enhances ROS creation	In vivo: significantly increased radiosensitivity