Cisplatin Induces Differentiation of Breast Cancer Cells

Abstract

Breast tumors are heterogeneous including cells with stem cell properties and more differentiated cells. This heterogeneity is reflected into the molecular breast cancer subtypes. Breast cancer stem cells are resistant to chemotherapy, thus recent efforts are focusing on identifying treatments that shift them toward a more differentiated phenotype, making them more susceptible to chemotherapy. We examined whether the drug cisplatin induces differentiation in breast cancer cell lines that represent different breast cancer subtypes. We used three cell lines representing triple-negative breast cancers, BT-549 and MDA-MB-231 (claudin-low), and MDA-MB-468 (basal-like), along with estrogen and progesterone receptor positive MCF-7 cells (luminal). Cisplatin was applied at 2.5, 5, 10, and 20 μM, and cell viability and proliferation were measured using MTS and BrdU assays, respectively. The effect of cisplatin on the cellular hierarchy was examined by flow cytometry, immunofluorescence and qRT-PCR. Cisplatin treatment of 10 and 20 μM reduced cell viability by 36–51% and proliferation capacity by 36–67%. Treatment with cisplatin resulted in 12–67% down-regulation of stem cell markers (CD49f, SSEA4) and 10–130% up-regulation of differentiation markers (CK18, SMA, β-tubulin). At the mRNA level, CD49f was down-regulated whilst β-tubulin was up-regulated in the claudin-low cell lines. SSEA4 protein expression decreased upon cisplatin treatment, but SSEA4 mRNA expression increased indicating a differential regulation of cisplatin at the post-transcriptional level. It is concluded that cisplatin reduces breast cancer cell survival and induces differentiation of stem/progenitor cell subpopulations within breast cancer cell lines. These effects indicate the potential of this drug to target specific chemotherapy-resistant cells within a tumor.

Platinum-Based Drugs Differentially Affect the Ultrastructure of Breast Cancer Cell Types

“…These apoptotic findings were consistent with other findings in which apoptosis was the major mechanism of cell death that appeared in MCF-7 cells following exposure to Cisplatin [18, 28]. Interestingly, the absence of nucleus in MDA-MB-231 after treatment with PBDs was observed which might be explained by the extrusion of nucleus as a way for cancer cells to die.…”

Cisplatin (CDDP) triggers cell death of MCF-7 cells following disruption of intracellular calcium ([Ca²⁺]_i) homeostasis

“…5 while the rate of necrosis did not increase significantly. Previous work of Prabhakaran et al (2013), using triple-negative BCs, BT-549, MDA-MB-231 and MDA-MB-468, along with estrogen and progesterone receptor positive MCF-7 cells, showed that the 10-20 μM CDDP treatment reduced cell viability by 36-51% and proliferation capacity by 36-67%. The authors concluded that cisplatin reduces BC cell survival showing the potential of this drug to target specific chemotherapy-resistant cells within a tumor (Prabhakaran et al, 2013).…”

“…BC are heterogeneous (Prabhakaran et al, 2013;Joensuu and Gligorov, 2012) while several risk factors have been associated with BC: age, geographic location, socio-economic status, reproductive events, hormones, lifestyle, family history of BC, mammographic density, previous benign breast disease, ionizing radiation, bone density, height, IGF-1 and prolactin levels, chemo-preventive agents (Eckstein and Haas, 2012;Dumitrescu and Cotarla, 2005;Florea and Büsselberg, 2013). Furthermore, the genetic and epigenetic backgrounds of the patients seem to play an important role in BC pathogenesis and response to chemotherapy (Normanno et al, 2009;Colombo et al, 2011) while gene expression signatures might be predictive for the patient outcome.…”

“…Thus, new therapy concepts are necessary to treat BC (Florea and Büsselberg, 2011Eckstein and Haas, 2012). Recent efforts target new treatments to make BC sensitive to chemotherapy (Prabhakaran et al, 2013) while some platinum salts are promising drugs for future BC therapies (Biersack et al, 2012). Furthermore, using combinations of these compounds with docetaxel has been proven to be effective in advanced triple-negative BCs (Hurley et al, 2013;Shamseddine and Farhat, 2011;Eckstein and Haas, 2012) and the combinations of CDDP/carboplatin/taxanes showed the highest efficacy and safety in first-line and second-line therapy (Shamseddine and Farhat, 2011).…”

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

“…Breast cancer, the leading cause of death among women in the world, representing 23% of all cancer cases, is a heterogenic disease at cellular and molecular levels 1,2 . Therefore, there is an urgent need for novel drugs with an improved efficacy against breast cancer cells with minimal toxicity on normal cells.…”