A Soft Coral-Derived Compound, 11-Dehydrosinulariolide, Induces G2/M Cell Cycle Arrest and Apoptosis in Small Cell Lung Cancer

Abstract

11-Dehydrosinulariolide, an active compound that is isolated from the cultured soft coral Sinularia flexibilis, has been suggested to show anti-tumor biological characteristics according to previous studies. However, its potential effect on small cell lung cancer (SCLC) remains unknown. The present study investigates the underlying mechanism for the treatment of SCLC in vitro and in vivo. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was applied to evaluate cell cycle distribution and apoptosis. The expression of proteins related to the cell cycle and apoptosis was analyzed by Western blot analysis. Additionally, an in vivo study was performed to determine the anti-SCLC effect on an H1688 subcutaneous tumor in a BALB/c nude mouse model. 11-Dehydrosinulariolide inhibited cell growth, triggered G2/M arrest and induced H1688 cell apoptosis in a dose- and time-dependent manner. Additionally, 11-dehydrosinulariolide caused the accumulation of p53 and Bax, accompanied by the activation of DNA damage-inducing kinases, including ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2). Moreover, 11-dehydrosinulariolide increased the activity of caspase-3 and -7, suggesting that caspases are involved in 11-dehydrosinulariolide-induced apoptosis. 11-Dehydrosinulariolide also increased the level of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibited the expression of phosphorylated Akt. In the in vivo study, the intraperitoneal injection of 11-dehydrosinulariolide at a dosage of 10 mg/kg significantly inhibited tumor growth compared with the control treatment. Together, the data indicate that 11-dehydrosinulariolide induces G (2)/M cell cycle arrest and apoptosis through various cellular processes, including the upregulation of p53 and Bax, activation of ATM and Chk2, activation of caspase-3 and -7, and accumulation of PTEN, leading to inhibition of the Akt pathway. These findings suggest that 11-dehydrosinulariolide might serve as a promising chemotherapy drug in the treatment of SCLC.

Identification of candidate genes associated with the pathogenesis of small cell lung cancer via integrated bioinformatics analysis

“…Previous studies (14,40) have also indicated that the cell cycle pathway is an important pathway involved in the development and progression of SCLC. It has also been demonstrated that certain associated drugs can restore the abnormal cell cycle in SCLC, thus playing anti-tumor roles (41).…”

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G0/G1 phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

“…Another pivotal mechanism that has contributed to the anti-tumor activity of chemotherapeutic drugs is cell cycle arrest, which accumulates cancer cells at a specific phase and halts the progress of the cell cycle (Lin et al, 2018). Our results showed that 9za could retard the cell population at G 0 /G 1 phase at low concentrations (<10 µM).…”

Polyphenolic Profile and Varied Bioactivities of Processed Taiwanese Grown Broccoli: A Comparative Study of Edible and Non-Edible Parts

“…Cancers are the consequence of cell-cycle dysregulation. Targeting the checkpoint signaling pathway, which generally leads to an arrest at the G1/S or G2/M phases, would be another effective therapeutic strategy [19]. Loss of MMP is closely linked to the activation of caspase-9, which plays a critical role in the initiation and maintenance of apoptosis [20].…”

“…Cell cycle analysis was undertaken to classify the cell population into four distinctive phases, comprising the subG1 phase, G0/G1 phase, S phase, and G2/M phase. The subG1 population is an indication of apoptotic cell death, and the two checkpoints are G1/S and G2/M transitions [19]. As shown in Figure 1, Caco-2 cells showed a significant increase of population in the subG1 phase from around 4% in the case of control to approximately 15% and 31% when exposed to broccoli extracts for 24 and 48 h, respectively.…”