Effects of gossypol on apoptosis­related gene expression in racially distinct triple­negative breast cancer cells.

Apoptosis is a gene­directed mechanism that regulates cell proliferation and maintains homeostasis. Moreover, an aberrant apoptotic process can lead to several pathological conditions, such as tumorigenesis and cancer metastasis. In the present study, the apoptotic effect of the natural polyphenol compound gossypol GOSS) was investigated in triple­negative breast cancer TNBC) cells. The effect of GOSS was evaluated in two cell lines representative of a Caucasian­American and African­American origin, MDA­MB­231 MM­231) and MDA­MB­468 MM­468), respectively. A similar response to both cytotoxicity and proliferation was observed in the two cell lines. However, MM­468 cells were 2­fold more sensitive to the apoptotic effect of the compound, which was accompanied by a longer delay in colony formation. Furthermore, GOSS was found to alter the mRNA expression of many apoptosis­related genes. The compound significantly upregulated growth arrest and DNA damage­inducible 45 alpha protein (GADD45A), tumor necrosis factor receptor superfamily 9 (TNFRSF9) and BCL2 interacting protein 3 BNIP3) in MM­231 cells. Similarly, GADD45A and BNIP3 were upregulated in MM­468 cells. A significant finding in this study is the profound 159­fold increase in TNF gene expression that was observed in MM­468 cells. Moreover, the apoptosis­suppressor gene baculoviral IAP repeat containing 5 BIRC5) was significantly repressed (by more than 90%) in both cell lines, as well as death­associated protein kinase 1 (DAPK1) in MM­231 cells and tumor protein 73 (TP73) in MM­468 cells. In conclusion, the data obtained in this study provide a molecular understanding of the GOSS­induced apoptosis effect and suggest the importance of this polyphenol compound targeted towards TNBC treatment, particularly in African­American women.

The inhibitory effects of plumbagin on the NF-қB pathway and CCL2 release in racially different triple-negative breast cancer cells.

Breast cancer (BC) is the second leading cause of death among women in the US, and its subtype triple-negative BC (TNBC) is the most aggressive BC with poor prognosis. In the current study, we investigated the anticancer effects of the natural product plumbagin (PL) on racially different TNBC cells. The PL effects were examined in two TNBC cell lines: MDA-MB-231 (MM-231) and MDA-MB-468 (MM-468), representing Caucasian Americans and African Americans, respectively. The results obtained indicate that PL inhibited cell viability and cell proliferation and induced apoptosis in both cell lines. Notably, MM-468 cells were 5-fold more sensitive to PL than MM-231 cells were. Testing PL and Taxol® showed the superiority of PL over Taxol® as an antiproliferative agent in MM-468 cells. PL treatment resulted in an approximately 20-fold increase in caspase-3 activity with 3 µM PL in MM-468 cells compared with an approximately 3-fold activity increase in MM-231 cells with 8 µM PL. Moreover, the results indicate a higher sensitivity to PL in MM-468 cells than in MM-231 cells. The results also show that PL downregulated CCL2 cytokine expression in MM-468 cells by 30% compared to a 90% downregulation in MM-231 cells. The ELISA results confirmed the array data (35% vs. 75% downregulation in MM-468 and MM-231 cells, respectively). Moreover, PL significantly downregulated IL-6 and GM-CSF in the MM-231 cells. Indeed, PL repressed many NF-қB-regulated genes involved in the regulation of apoptosis, proliferation, invasion, and metastasis. The compound significantly downregulated the same genes (BIRC3, CCL2, TLR2, and TNF) in both types of cells. However, PL impacted five more genes in MM-231 cells, including BCL2A1, ICAM1, IKBKE, IL1ß, and LTA. In conclusion, the data obtained in this study indicate that the quinone compound PL could be a novel cancer treatment for TNBC in African American women.