Picrasidine G decreases viability of MDA-MB 468 EGFR-overexpressing triple-negative breast cancer cells through inhibition of EGFR/STAT3 signaling pathway

• Published in: Bioorganic & Medicinal Chemistry Letters Vol. 27; no. 11; pp. 2608 - 2612
• Main Authors: Yamashita, Naoya, Kondo, Manami, Zhao, Shuai, Li, Wei, Koike, Kazuo, Nemoto, Kiyomitsu, Kanno, Yuichiro
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2017; Elsevier BV
• Subjects: Alkaloids; Alkaloids - chemistry; Alkaloids - toxicity; Apoptosis; Apoptosis - drug effects; Breast cancer; Carbolines; Carbolines - chemistry; Carbolines - toxicity; Caspase; Caspase 3; Caspase 3 - metabolism; Cell Line, Tumor; Cell Survival; Cell Survival - drug effects; Epidermal growth factor receptor; ErbB Receptors; Female; G1 Phase Cell Cycle Checkpoints; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; Interleukin-6; Interleukin-6 - pharmacology; Phosphorylation; Phosphorylation - drug effects; Poly(ADP-ribose) Polymerases; Poly(ADP-ribose) Polymerases - metabolism; Receptor, Epidermal Growth Factor - metabolism; Signal transducer and activator of transcription 3; Signal Transduction; Signal Transduction - drug effects; STAT3 Transcription Factor; STAT3 Transcription Factor - metabolism; Triple Negative Breast Neoplasms; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Caspase; Breast cancer; Epidermal growth factor receptor; Signal transducer and activator of transcription 3; Apoptosis
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2017.03.061

[Display omitted] •Picrasidine G decreased viability of EGFR-overexpressing triple-negative breast cancer cells.•Picrasidine G increased caspase-dependent apoptotic cells.•Picrasidine G inhibited EGF-induced STAT3 phosphorylation. Targeted therapy is unavailable for treating patients with triple-negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers. Overexpression of epidermal growth factor receptor (EGFR) is observed in approximately 30–60% of TNBCs. Therefore, developing novel strategies for inhibiting EGFR signaling is required. In the present study, a natural compound library was screened to identify molecules that target TNBCs that overexpress EGFR. Picrasidine G (PG), a naturally occurring dimeric alkaloid produced by Picrasma quassioides, decreased the viability of the MDA-MB 468 cell line (TNBCEGFR+) compared with other breast cancer cell lines. PG treatment increased markers of apoptosis, including chromatin condensation, sub-G1 population, cleavage of caspase 3 and cleavage of poly (ADP-ribose) polymerase (PARP). PG inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and inhibited transcription of the STAT3-target gene encoding survivin. Further, PG inhibited EGF-induced STAT3 phosphorylation but not interleukin-6 (IL-6)-induced STAT3 phosphorylation. These results suggest that PG may contribute to the development of targeted therapy of patients with EGFR-overexpressing TNBC.