PMID- 34299315 OWN - NLM STAT- MEDLINE DCOM- 20210806 LR - 20211206 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 14 DP - 2021 Jul 19 TI - Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel. LID - 10.3390/ijms22147694 [doi] LID - 7694 AB - 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-beta (TGF-beta) 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. FAU - Gangapuram, Madhavi AU - Gangapuram M AUID- ORCID: 0000-0002-4877-9127 AD - Pharmaceutical Sciences Division, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USA. FAU - Mazzio, Elizabeth A AU - Mazzio EA AD - Pharmaceutical Sciences Division, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USA. FAU - Redda, Kinfe K AU - Redda KK AUID- ORCID: 0000-0002-3526-8387 AD - Pharmaceutical Sciences Division, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USA. FAU - Soliman, Karam F A AU - Soliman KFA AUID- ORCID: 0000-0002-0600-1085 AD - Pharmaceutical Sciences Division, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USA. LA - eng GR - U54 MD007582/MD/NIMHD NIH HHS/United States GR - U54 MD007582./MD/NIMHD NIH HHS/United States PT - Comparative Study PT - Journal Article DEP - 20210719 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Antineoplastic Agents) RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (Benzamides) RN - 0 (Cytostatic Agents) RN - 0 (GM-4-53) RN - 0 (Isoquinolines) RN - 0 (Tetrahydroisoquinolines) RN - P88XT4IS4D (Paclitaxel) SB - IM MH - Antineoplastic Agents/pharmacology MH - Antineoplastic Agents, Phytogenic/pharmacology MH - Benzamides/*pharmacology MH - Cell Cycle/drug effects MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cytostatic Agents/*pharmacology MH - Drug Discovery MH - Female MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Isoquinolines/*pharmacology MH - Paclitaxel/*pharmacology MH - Tetrahydroisoquinolines/pharmacology MH - Triple Negative Breast Neoplasms/*drug therapy/genetics/pathology PMC - PMC8306781 OTO - NOTNLM OT - cancer OT - cytostatic OT - drug discovery COIS- The authors declare no conflict of interest. EDAT- 2021/07/25 06:00 MHDA- 2021/08/07 06:00 PMCR- 2021/07/19 CRDT- 2021/07/24 01:03 PHST- 2021/05/24 00:00 [received] PHST- 2021/07/09 00:00 [revised] PHST- 2021/07/16 00:00 [accepted] PHST- 2021/07/24 01:03 [entrez] PHST- 2021/07/25 06:00 [pubmed] PHST- 2021/08/07 06:00 [medline] PHST- 2021/07/19 00:00 [pmc-release] AID - ijms22147694 [pii] AID - ijms-22-07694 [pii] AID - 10.3390/ijms22147694 [doi] PST - epublish SO - Int J Mol Sci. 2021 Jul 19;22(14):7694. doi: 10.3390/ijms22147694.