The effect of Dinaciclib and Palbociclib on normal and breast cancer cells in 2D and 3D culture.

Abstract

Triple-negative breast cancer (TNBC), which accounts for 15–20percent of all breast cancers, are extremely aggressive and have a poor prognosis due to the high tendency for metastatic progression and absence of specific targeted treatment. Since deregulation of cell cycle control is a hallmark of cancer, targeting cell cycle regulators such as cyclin- dependent kinases (CDK) may be an efficacious therapeutic approach for TNBC treatment. Palbociclib is a specific inhibitor of CDK4-6 and has been shown to induce senescence in several types of cancer. Dinaciclib, a CDK2 inhibitor, has shown promising antitumor activity in preclinical studies in broad spectrum of cell lines and in early phase clinical trials of hematological and solid malignancies. Here we examined the effect of Dinaciclib and Palbociclib, added alone, in combination or in tandem in a 2D as well as in 3D model of TNBC which shares similar properties to its in vivo counterpart. Our preliminary data showed that treatment of TNBC MDA- MB 231 cells with Dinaciclib, Palbociclib and combination for 48 hours decreased cell proliferation. Dinaciclib and combination increased the percentage of cells in pre-G1 whereas Palbociclib induced cell cycle arrest in G0-G1. Palbociclib significantly increased the percentage of Senescence associated β- galactosidase positive cells when treated for a longer period compared to those untreated or treated with Dinaciclib, combination or tandem. The drugs effect was also assessed in HMT3552 series including normal S1, intermediate Cx43 KO-S1, and cancer T4-2 cells. Our preliminary data suggested that treatment of S1, Cx43 KO-S1 and T4-2 cells cultured in 2D decreased cell proliferation. This decrease was progressive and became more significant after 10 days of treatment. Moreover, dual drug combination had most potent effect compared with single treatment and tandem. Preliminary data of Western-blot analysis in 2D culture proposed that Palbociclib and combination increased the expression of p21 in S1 and T4-2 cells co