Next Article in Journal
Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease
Previous Article in Journal
STAT1 Is Required for Decreasing Accumulation of Granulocytic Cells via IL-17 during Initial Steps of Colitis-Associated Cancer
Previous Article in Special Issue
Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells
Article

Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel

Pharmaceutical Sciences Division, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Antonella Zannetti
Int. J. Mol. Sci. 2021, 22(14), 7694; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147694
Received: 24 May 2021 / Revised: 9 July 2021 / Accepted: 16 July 2021 / Published: 19 July 2021
The absence of chemotherapeutic target hormone receptors in breast cancer is descriptive of the commonly known triple-negative breast cancer (TNBC) subtype. TNBC remains one of the most aggressive invasive breast cancers, with the highest mortality rates in African American women. Therefore, new drug therapies are continually being explored. Microtubule-targeting agents such as paclitaxel (Taxol) interfere with microtubules dynamics, induce mitotic arrest, and remain a first-in-class adjunct drug to treat TNBC. Recently, we synthesized a series of small molecules of substituted tetrahydroisoquinolines (THIQs). The lead compound of this series, with the most potent cytostatic effect, was identified as 4-Ethyl-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl) benzamide (GM-4-53). In our previous work, GM-4-53 was similar to paclitaxel in its capacity to completely abrogate cell cycle in MDA-MB-231 TNBC cells, with the former not impairing tubulin depolymerization. Given that GM-4-53 is a cytostatic agent, and little is known about its mechanism of action, here, we elucidate differences and similarities to paclitaxel by evaluating whole-transcriptome microarray data in MDA-MB-231 cells. The data obtained show that both drugs were cytostatic at non-toxic concentrations and caused deformed morphological cytoskeletal enlargement in 2D cultures. In 3D cultures, the data show greater core penetration, observed by GM-4-53, than paclitaxel. In concentrations where the drugs entirely blocked the cell cycle, the transcriptome profile of the 48,226 genes analyzed (selection criteria: (p-value, FDR p-value < 0.05, fold change −2< and >2)), paclitaxel evoked 153 differentially expressed genes (DEGs), GM-4-53 evoked 243 DEGs, and, of these changes, 52/153 paclitaxel DEGs were also observed by GM-4-53, constituting a 34% overlap. The 52 DEGS analysis by String database indicates that these changes involve transcripts that influence microtubule spindle formation, chromosome segregation, mitosis/cell cycle, and transforming growth factor-β (TGF-β) signaling. Of interest, both drugs effectively downregulated “inhibitor of DNA binding, dominant negative helix-loop-helix” (ID) transcripts; ID1, ID3 and ID4, and amphiregulin (AREG) and epiregulin (EREG) transcripts, which play a formidable role in cell division. Given the efficient solubility of GM-4-53, its low molecular weight (MW; 296), and capacity to penetrate a small solid tumor mass and effectively block the cell cycle, this drug may have future therapeutic value in treating TNBC or other cancers. Future studies will be required to evaluate this drug in preclinical models. View Full-Text
Keywords: drug discovery; cytostatic; cancer drug discovery; cytostatic; cancer
Show Figures

Figure 1

MDPI and ACS Style

Gangapuram, M.; Mazzio, E.A.; Redda, K.K.; Soliman, K.F.A. Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel. Int. J. Mol. Sci. 2021, 22, 7694. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147694

AMA Style

Gangapuram M, Mazzio EA, Redda KK, Soliman KFA. Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel. International Journal of Molecular Sciences. 2021; 22(14):7694. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147694

Chicago/Turabian Style

Gangapuram, Madhavi, Elizabeth A. Mazzio, Kinfe K. Redda, and Karam F.A. Soliman 2021. "Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel" International Journal of Molecular Sciences 22, no. 14: 7694. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147694

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop