A novel synthetic iminoquinone, BA-TPQ, as an anti-breast cancer agent: in vitro and in vivo activity and mechanisms of action.
Herein, we report our examination of the anti-breast cancer activity of a novel synthetic compound, 7-(benzylamino)-1, 3, 4, 8-tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one (BA-TPQ). This agent is an analog of a naturally occurring marine compound, and was found to be the most active out of more than 40 related compounds. We investigated the in vitro activity of BA-TPQ on the survival, proliferation, and apoptosis of breast cancer cells using the MTT and BrdUrd assays, and Annexin/Annexin-PI staining and flow cytometry. The in vivo anti-cancer effects of BA-TPQ were evaluated in xenograft models of breast cancer. Finally, the mechanisms of action of the compound were also assessed by cDNA microarrays, RT-PCR and Western blotting. In a dose-dependent manner, BA-TPQ inhibited cell growth and induced apoptosis and cell cycle arrest in human MCF-7 and MDA-MB-468 breast cancer cells in vitro, and showed in vivo efficacy in mice bearing MCF-7 or MDA-MB-468 xenograft tumors. We demonstrated that BA-TPQ modifies the expression of numerous molecules involved in cell cycle progression and apoptosis. Similar changes in protein expression were observed in vitro and in vivo, as determined by examination of cells and excised xenograft tumors. Our preclinical data indicate that BA-TPQ is a potential therapeutic agent for breast cancer that has multiple hormone-, Her2-, and p53-independent mechanisms of action, providing a basis for further development of the compound as a novel anticancer agent.
Wang
Wei
W
Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Rayburn
Elizabeth R
ER
Velu
Sadanandan E
SE
Chen
Deng
D
Nadkarni
Dwayaja H
DH
Murugesan
Srinivasan
S
Chen
Dongquan
D
Zhang
Ruiwen
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
C553817:7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D011758:Pyrroles; D015363:Quinolones