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Pyrrolidine Dithiocarbamate, a Potent NF‐Kappa‐β Inhibitor, Induces Cell Cycle Dysregulation and Suppression of Autophagy in Triple‐Negative Breast Cancer Cells
Author(s) -
Tomblin Justin,
Mehmi Inderjit,
Salisbury Travis
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.945.9
Subject(s) - pyrrolidine dithiocarbamate , triple negative breast cancer , cancer research , cyclin d1 , viability assay , estrogen receptor , programmed cell death , mg132 , apoptosis , cyclin dependent kinase , cancer cell , chemistry , cancer , breast cancer , cell cycle , biology , medicine , nf κb , proteasome inhibitor , biochemistry
Triple‐negative breast cancer cells (BCCs) lack the estrogen, progesterone, and ERBB2 receptors. As such, these cells do not respond well to standard chemotherapy regimens such as hormone based therapies like tamoxifen and aromatase inhibitors. Triple‐negative cancers require combinatorial therapies, which are often unsuccessful and are associated with marked toxicity. New drug therapy effective against these cancers is, thus, of great importance. Here, for the first time, we show pyrrolidine dithiocarbamate (PDTC), a potent NF‐Kappa‐β inhibitor, dysregulates the cell cycle by decreasing expression of cyclin‐dependent kinases (CDK)‐4 and 5 while simultaneously inducing cyclin D1 (CCND1) in MDA‐MB‐231 and MDA‐MB‐436 BCCs. We correlated this with reduction in activated Retinoblastoma (Rb) protein. Changes in cell morphology were noted by 24hrs, and cell viability following PDTC treatment (1μM‐100μM) was reduced compared to control cells. To observe whether apoptosis was occurring, levels of nuclear protein poly (ADP‐ribose) polymerase (PARP), which undergoes cleavage during apoptosis, were assayed and were not significantly different from control cells following 24hr PDTC treatment. Interestingly, we noted decreased levels of several proteins involved in autophagy, a stress response cells undergo which when inhibited leads to cell death. Currently, we are investigating whether PDTC's tumoricidal effects occur through this potential mechanism.