Selective Agonists of Nuclear Retinoic Acid Receptor Gamma Inhibit Growth of HCS‐2/8 Chondrosarcoma Cells

Abstract

Chondrosarcoma is the second most common primary bone sarcoma. Treatment of chondrosarcoma is limited to surgery due to radiation and chemotherapy resistance of this cancer. An ideal treatment for chondrosarcoma would be a well-tolerated, minimally invasive local or systemic treatment modality to halt or slow tumor growth prior to resection of local, unresectable local, or metastatic disease. Palovarotene, an agonist of nuclear retinoic acid receptor γ (RARγ) has shown therapeutic action for treatment of heterotopic ossification and osteochondroma without serious adverse effects in animal models. We hypothesized that selective agonists of RARγ would have an inhibitory effect on chondrosarcoma. All human chondrosarcoma specimens expressed RARγ as determined by immunohistochemical staining. The ΗCS-2/8 chondrosarcoma cell line, established from low-grade human chondrosarcoma, was used to examine the actions of RARγ agonists. In ΗCS2/8 pellet cultures, RARγ agonist treatment reduced the mass size and significantly decreased total glycosaminoglycan, protein amounts, and gene expression levels of cartilage matrix molecules when compared with control groups. Systemic treatment with RARγ agonists significantly inhibited the growth of ΗCS-2/8 cell transplants in vivo. Furthermore, local injection of RARγ agonist-loaded poly-lactic acid nanoparticles induced regression of the mass size of the transplants. Histologic analysis demonstrated that RARγ agonist treatment inhibited cell proliferation activity and stimulated encapsulation of the tumor. These findings indicate that RARγ agonists, including palovarotene, may have an anti-tumor effect on low-grade chondrosarcomas.

Selective Retinoic Acid Receptor γ Antagonist 7C is a Potent Enhancer of BMP-Induced Ectopic Endochondral Bone Formation

“…We selected the 7C compounds for this purpose because 7C stimulates the ectopic bone formation via systemic administration ( Uchibe et al, 2017 ) and has similar chemical properties in size, organophilicity and structure to those of NRX204647 ( Supplementary Figure S1 ). The NRX204647 loaded PLA-NPs successfully inhibit chondrosarcoma growth with minimum local tissue damage ( Shield et al, 2020 ). To examine the action of 7C-NPs on bone formation, 7C-NPs or blank-NPs were mixed into the BMP-2 pellets.…”

“…In addition, by applying the drug locally, we could minimize systemic side-effects. Furthermore, we recently formulated NRX204647-loaded PLA-NP which successfully inhibited chondrosarcoma growth with minimum local tissue damage ( Shield et al, 2020 ). Since the chemical properties of NRX204647 and 7C are quite similar in size, organophilicity, and structure ( Supplementary Figure S1 ), we predicted that PLA-NP is a suitable drug vehicle for our study.…”

“…Retinoid-loaded NPs were formulated using a modification of the emulsification-solvent evaporation method with albumin as a colloidal stabilizer ( Chorny et al, 2010 ; Chorny et al, 2012 ). Synthetic retinoid loaded PLA-NPs are biodegradable and release the active drug for a prolonged time period ( Shield et al, 2020 ).…”

“…The NRX204647 loaded PLA-NPs successfully inhibit chondrosarcoma growth with minimum local tissue damage (Shield et al, 2020). To examine the action of 7C-NPs on bone formation, 7C-NPs or blank-NPs were mixed into the BMP-2 pellets.…”

Retinoic Acid Receptor Gamma (RARγ) Promotes Cartilage Destruction through Positive Feedback Activation of NF-κB Pathway in Human Osteoarthritis

“…Several studies have reported that RAR γ plays an essential role in cartilage matrix and proteoglycan homeostasis [ 19 ]. RAR γ activation could exhibit an antitumor effect on chondrosarcomas through promoting cartilage matrix degradation, inhibiting matrix synthesis, and inducing cell death [ 20 , 21 ]. RAR γ could regulate the expression of specific genes in the differentiation of mice hypertrophic chondrocytes, such as Tg2, Mmp13, Col10A1, and Ccn2 [ 22 ].…”