Potentiation of in vitro and in vivoantitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells

Abstract

BackgroundIn the present study, we show that the combination of doxorubicin with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces extensive apoptosis than either drug alone in H-460 human NSCLC cells.MethodsSynergistic effects of P276-00 and doxorubicin on growth inhibition was studied using the Propidium Iodide (PI) assay. The doses showing the best synergistic effect was determined and these doses were used for further mechanistic studies such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of the combination was evaluated using the H-460 xenograft model.ResultsThe combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced G2/M arrest and induction of apoptosis was observed in the combination treatment. This was associated with induction of tumor suppressor protein p53 and reduction of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced COX-2, a NF-κB target and Cdk-1, a target of P276-00, which was downregulated by P276-00 in the combination. Doxorubicin when combined with P276-00 in a sequence-specific manner significantly inhibited tumor growth, compared with either doxorubicin or P276-00 alone in H-460 xenograft model.ConclusionThese findings suggest that this combination may increase the therapeutic index over doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-κB signaling and inhibition of Cdk-1 which is involved in cell cycle progression.

A Phase II, Single-Arm, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of P276-00, a Cyclin-Dependent Kinase Inhibitor, in Patients With Relapsed or Refractory Mantle Cell Lymphoma

“…8 Others have demonstrated similar potentiating activity of P276-00 in combination with doxorubicin in non-small cell lung carcinoma cell lines and xenografts as well as with gemcitabine in pancreas cancer xenografts. 16-18 In fact, the latter of these strategies was being investigated in a phase I/II clinical trial in patients with advanced pancreatic cancer, in which P276-00 was well-tolerated in these patients when administered with gemcitabine with mild trends of efficacy. 19 Others have shown potential deleterious effects of combining DNA-damaging agents with a CDK4/6 inhibitor (PD0332991; Pfizer, Inc.) in a mouse xenograft model of breast cancer.…”

Mussel-inspired protein-mediated surface functionalization of electrospun nanofibers for pH-responsive drug delivery

“…The cytotoxicity results further confirmed pH-responsive release of DOX from polydopamine-coated PCL nanofibers and toxicology data which was reported by Rathos et al . using propidium iodide assay [39]. …”

Can marine‐derived fungus Neosartorya siamensis KUFA 0017 extract and its secondary metabolites enhance antitumor activity of doxorubicin? An in vitro survey unveils interactions against lung cancer cells

“…Doxorubicin (Dox) is an anthracycline which was discovered in the 1960s and is one of the most successful anticancer drugs in the treatment of several tumors. The mechanism of action of Dox has been extensively studied, and two main mechanisms have been proposed: intercalation into DNA, which consequently blocks the enzyme topoisomerase IIα and induction of free radicals . However, cardiotoxicity and drug resistance are the major limitations for the clinical use of Dox .…”