Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclin-dependent kinase 4 as a potential target

Abstract

Background Chondrosarcoma is a malignant cartilaginous neoplasm of the bone which resistant to radiation therapy and chemotherapy. Cyclin-dependent kinase 4 (CKD4) is highly expressed in human cancer, and palbociclib, the inhibitor of CDK4 has been used clinically under FDA approval for application in cancer therapeutic remedies. However, the level of CDK4 and the treatment possibility in chondrosarcoma require further exploration. Thus, we aim to investigate the level of CDK4 and accompanying therapeutic effects of palbociclib in chondrosarcoma. Methods We used immunohistochemistric analysis to evaluate human CDK4 productions in chondrosarcoma tissues. The inhibitory expression of CDK4 by siRNA or palbociclib on cell proliferation, invasion, migration, apoptosis and cycle arrest of chondrosarcoma were determined by MTT, wound healing, transwell and flow cytometry. CDK4/Rb signaling pathway were determined by western blot and Immunofluorescence assay. The inhibition effect of palbociclib on tumor growth within the bone were determined by bioluminescence imaging in vivo. Results CDK4 was found to express significantly in human chondrosarcoma samples. The enhanced levels of CDK4 were interlinked with malignant metastasis and undesirable prognosis of chondrosarcoma patients. CDK4 was also highly expressed in human chondrosarcoma cell lines and its inhibition by specific siRNA and palbociclib lead to a decrease in cell proliferation, accompanied by the phosphorylation of Rb. Furthermore, palbociclib also induced cell cycle arrest in G1 phase and decreased cell migration and invasion via CDK4/Rb signaling pathway. Administration of palbociclib in vivo could reduce tumor burden in chondrosarcoma. Conclusions In summary, these data highlight CDK4 inhibitors, such as palbociclib, as potential promising therapeutics in the treatment of human chondrosarcoma.

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

“…Interestingly, the MEK/ERK cascade has been demonstrated to control cell motility in HCC cell models, through a mechanism involving urokinase receptor (uPAR)mediated phosphorylation/activation of p70S6K (65). Previous studies have shown that both regorafenib, in HCC and gastric cancer (66,67), as well as palbociclib, in other cancer types (68,69), can affect cell motility. Here, we demonstrate that palbociclib and regorafenib combination reduced migration and invasion more efficaciously than individual treatments, possibly through inhibition of p70S6K activity.…”

Rubidium Chloride Targets Jnk/p38-Mediated NF-κB Activation to Attenuate Osteoclastogenesis and Facilitate Osteoblastogenesis

“…The viability of BMMs was assessed with the Cell Counting Kit-8 (CCK-8) method (Luo et al., 2018; Ouyang et al., 2018, 2019a,b; Xiao et al., 2018; Zhang et al., 2018). Briefly, BMMs were first seeded into 96-well plates at a density of 1.0 × 10 5 cells/well for 24 h. Next, BMMs were treated with corresponding concentrations of RbCl (0, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.8, and 25.6 mM) for up to 4 days.…”

Translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20) facilitates cancer aggressiveness and therapeutic resistance in chondrosarcoma

“…Since TOMM20 overexpression increased markers of cancer aggressiveness including proliferation and resistance to apoptosis, we wanted to determine if TOMM20 overexpression can lead to resistance to anticancer drugs that target proliferating cells that have been studied in the context of chondrosarcoma such as Gemcitabine, Doxorubicin and Palbociclib. Gemcitabine and Doxorubicin are commonly used agents to treat sarcomas [11] [19] and recently the cyclin dependent kinase 4/6 inhibitor Palbociclib that Journal Pre-proof targets proliferating cells has shown promise in chondrosarcoma preclinical models [38]. Figure 4B) (p<0.05).…”