Targeting CDKs with Roscovitine Increases Sensitivity to DNA Damaging Drugs of Human Osteosarcoma Cells

Abstract

Cyclin-dependent kinase 2 (CDK2) has been reported to be essential for cell proliferation in several human tumours and it has been suggested as an appropriate target to be considered in order to enhance the efficacy of treatment regimens based on the use of DNA damaging drugs. We evaluated the clinical impact of CDK2 overexpression on a series of 21 high-grade osteosarcoma (OS) samples profiled by using cDNA microarrays. We also assessed the in vitro efficacy of the CDKs inhibitor roscovitine in a panel of drug-sensitive and drug-resistant human OS cell lines. OS tumour samples showed an inherent overexpression of CDK2, and high expression levels at diagnosis of this kinase appeared to negatively impact on clinical outcome. CDK2 expression also proved to be relevant for in vitro OS cells growth. These findings indicated CDK2 as a promising candidate therapeutic marker for OS and therefore we assessed the efficacy of the CDKs-inhibitor roscovitine in both drug-sensitive and -resistant OS cell lines. All cell lines resulted to be responsive to roscovitine, which was also able to increase the activity of cisplatin and doxorubicin, the two most active DNA damaging drugs used in OS chemotherapy. Our results indicated that combined treatment with conventional OS chemotherapeutic drugs and roscovitine may represent a new candidate intervention approach, which may be considered to enhance tumour cell sensitivity to DNA damaging drugs.

Inhibition of cyclin‐dependent kinase activity exacerbates H2O2‐induced DNA damage in Kindler syndrome keratinocytes

“…CDKs also play an important role in controlling the response to DNA damage, and we show that roscovitine, a pan‐CDK inhibitor, can exacerbate both the cell cycle arrest and DNA damage induced by H 2 O 2 in KS keratinocytes. This has previously been reported for roscovitine in the context of DNA damage induced by chemotherapeutic agents . CDK1 is involved in the DNA double‐strand break homologous recombination repair pathway.…”

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

“…A major concern for all cardioprotective strategies against chemotherapy toxicity is the potential of interfering with the antitumor activity. Although our data suggested that genetic or pharmacologic inhibition of CDK2 attenuated DOX-induced cardiotoxicity, the same strategy has been shown to potentiate DOX anticancer efficacy in a variety of cancer cell lines by hindering DNA repair (37), inducing autophagy (38), or triggering apoptosis (39). Compared with DOX alone, combined treat-CDK2 inhibition alleviates doxorubicin cardiotoxicity ment with roscovitine and DOX significantly reduced tumor volume and improved survival in breast cancer xenograft models (17,40).…”

Cisplatin Resistance in Osteosarcoma: In vitro Validation of Candidate DNA Repair-Related Therapeutic Targets and Drugs for Tailored Treatments

“…Indeed, a variety of regulators including kinases, phosphatases, ubiquitin ligases, deubiquitinases, and other protein modifying enzymes, have been shown to modulate the activity and levels of key proteins belonging to different DNA repair pathways (13). In particular, protein kinases have been indicated to be involved or interfere with response to druginduced DNA damages (13), despite their actual role in this process must be carefully investigated and validated inside each specific tumor type and only few preliminary information has been reported for OS so far (14,15).…”

“…The interplay between DNA damage response and the proliferation machinery is based on the activity of several protein kinases, which in some tumors have been demonstrated to be involved in CDDP resistance (13). In human OS cells, we have obtained evidence of a possible involvement of aurora kinases in CDDP resistance (14) and of cyclin-dependent kinases (CDKs) in repair of CDDP-induced DNA damages (15), but this field of research still remains open.…”