[6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascades is considered to be a rational therapeutic and preventive strategy for the management of NSCLC. Our initial molecular target-oriented virtual screening revealed that the ginger components, including [6]-shogaol, [6]-paradol and [6]-gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, [6]-shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, [6]-shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclin D1/3, which are target proteins in the Akt signaling pathway. The induction of apoptosis in NCI-H1650 cells by [6]-shogaol corresponded with the cleavage of caspase-3 and caspase-7. Moreover, intraperitoneal administration of [6]-shogaol inhibited the growth of NCI-H1650 cells as tumor xenografts in nude mice. [6]-Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that [6]-shogaol can be exploited for the prevention and/or treatment of NSCLC.

6-Shogaol from Dried Ginger Inhibits Growth of Prostate Cancer Cells Both In Vitro and In Vivo through Inhibition of STAT3 and NF-κB Signaling

“…Given that 6-SHO effectively inhibited the growth of prostate cancer cells regardless of STAT3 expression or activity, multiple mechanisms are likely involved in its effects on prostate cancer cell survival, including effects on STAT3, NF-kB, and possibly other signaling pathways. In this regard, it has been reported that 6-SHO induces apoptosis by generation of reactive oxygen species in human colorectal cancer cells, by directly regulating Akt1/2 in nonsmall cell lung carcinoma cells and by modulation of estrogen receptor stress in hepatocellular carcinoma cells (23,32,43). In addition, as shown in Fig.…”

6‐shogaol induces apoptosis and enhances radiosensitivity in head and neck squamous cell carcinoma cell lines

“…In colon and breast cancer cell lines, apoptosis has been reported after treatment with 10‐μM 6‐shogaol (Tan et al, ). Induction of apoptosis was further proven in prostate cancer (Saha et al, ), lung cancer (Kim et al, ), leukemia (Liu, Peng, Zhou, et al, ), and hepatocellular carcinoma (Hu, Zhou, Peng, et al, ) cell lines.…”

Diet in lung cancer: back to natural and healthy food

“…Shogaol suppresses the proliferation of NSCLC cells by inducing cycle arrest (G1 and G2/M) and apoptosis [44]. Despite being more common and spreading more slowly than SCLC, most of NSCLC are diagnosed only when the cancer has metastasized; also, primary and secondary resistance limits therapeutic success.…”

“…Despite being more common and spreading more slowly than SCLC, most of NSCLC are diagnosed only when the cancer has metastasized; also, primary and secondary resistance limits therapeutic success. Adopting appropriate preventing strategies might reduce the incidence and mortality from NSCLC [44].…”