Forskolin improves sensitivity to doxorubicin of triple negative breast cancer cells via Protein Kinase A-mediated ERK1/2 inhibition

• Published in: Biochemical pharmacology Vol. 152; pp. 104 - 113
• Main Authors: Illiano, Michela, Sapio, Luigi, Salzillo, Alessia, Capasso, Lucia, Caiafa, Ilaria, Chiosi, Emilio, Spina, Annamaria, Naviglio, Silvio
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-06-2018
• Subjects: Cell Line, Tumor; Colforsin - pharmacology; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Doxorubicin; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Flavonoids - pharmacology; Forskolin; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Natural compounds; Protein Kinase A; Protein Kinase Inhibitors - pharmacology; Triple negative breast cancer; Triple Negative Breast Neoplasms - drug therapy; Natural compounds; Doxorubicin; Protein Kinase A; Triple negative breast cancer; Forskolin
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2018.03.023

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Triple negative breast cancer (TNBC) is an invasive, metastatic, highly aggressive tumor. Cytotoxic chemotherapy represents the current treatment for TNBC. However, relapse and chemo-resistance are very frequent. Therefore, new therapeutic approaches that are able to increase the sensitivity to cytotoxic drugs are needed. Forskolin, a natural cAMP elevating agent, has been used for several centuries in medicine and its safeness has also been demonstrated in modern studies. Recently, forskolin is emerging as a possible novel molecule for cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of MDA-MB-231 and MDA-MB-468 TNBC cells to doxorubicin through MTT assay, flow cytometry-based assays (cell-cycle progression and cell death), cell number counting and immunoblotting experiments. We demonstrate that forskolin strongly enhances doxorubicin-induced antiproliferative effects by cell death induction. Similar effects are observed with IBMX and isoproterenol cAMP elevating agents and 8-Br-cAMP analog, but not by using 8-pCPT-2′-O-Me-cAMP Epac activator. It is important to note that the forskolin-induced potentiation of sensitivity to doxorubicin is accompanied by a strong inhibition of ERK1/2 phosphorylation, is mimicked by ERK inhibitor PD98059 and is prevented by pre-treatment with Protein Kinase A (PKA) and adenylate cyclase inhibitors. Altogether, our data indicate that forskolin sensitizes TNBC cells to doxorubicin via a mechanism depending on the cAMP/PKA-mediated ERK inhibition. Our findings sustain the evidence of anticancer activity mediated by forskolin and encourage the design of future in-vivo/clinical studies in order to explore forskolin as a doxorubicin sensitizer for possible use in TNBC patients.