BCI induces apoptosis via generation of reactive oxygen species and activation of intrinsic mitochondrial pathway in H1299 lung cancer cells

Abstract

The compound (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) is known as an inhibitor of dual specific phosphatase 1/6 and mitogen-activated protein kinase. However, its precise anti-lung cancer mechanism remains unknown. In this study, the effects of BCI on the viability of non-small cell lung cancer cell lines NCI-H1299, A549, and NCI-H460 were evaluated. We confirmed that BCI significantly inhibited the viability of p53(-) NCI-H1299 cells as compared to NCI-H460 and A549 cells, which express wild-type p53. Furthermore, BCI treatment increased the level of cellular reactive oxygen species and pre-treatment of cells with N-acetylcysteine markedly attenuated BCI-mediated apoptosis of NCI-H1299 cells. BCI induced cellular morphological changes, inhibited viability, and produced reactive oxygen species in NCI-H1299 cells in a dose-dependent manner. BCI induced processing of caspase-9, caspase-3, and poly ADP-ribose polymerase as well as the release of cytochrome c from the mitochondria into the cytosol. In addition, BCI downregulated Bcl-2 expression and enhanced Bax expression in a dose-dependent manner in NCI-H1299 cells. However, BCI failed to modulate the expression of the death receptor and extrinsic factor caspase-8 and Bid, a linker between the intrinsic and extrinsic apoptotic pathways in NCI-H1299 cells. Thus, BCI induces apoptosis via generation of reactive oxygen species and activation of the intrinsic pathway in NCI-H1299 cells.

The In Vitro Anti-Tumor Activity of Phycocyanin against Non-Small Cell Lung Cancer Cells

“…The apoptotic percentage of H460 cells reached 3.72 ± 0.98% with phycocyanin treatment, which was significantly different than that in control cells, but markedly lower than that in H1299 (11.3 ± 0.16%) and LTEP-A2 cells (14.5 ± 0.68%). It is worth noting that Shin et al discovered that (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI, an inhibitor of dual specific phosphatase 1/6 and mitogen-activated protein kinase) significantly inhibits the viability of H1299 cells as compared to H460 cells [ 45 ], suggesting that different mechanisms might exist in lung adenocarcinoma (H1299 and LTEP-A2 cells) and undifferentiated large cell lung carcinoma (H460 cells) cell lines. Particularly, the transcription and protein levels of two apoptotic markers (Bcl-2 and Bcl-xL) were not consistently expressed in H460 cells ( Figure 3 ), which further supports the above hypothesis.…”

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

“…In NCI-H1299 cells, BCl could downregulate the level of Bcl-2 protein and upregulate the Bax protein expression, thereby promoting the release of Cyt-C and activating caspase 8 to trigger apoptosis. 89 …”

“…In NCI-H1299 cells, BCl could downregulate the level of Bcl-2 protein and upregulate the Bax protein expression, thereby promoting the release of Cyt-C and activating caspase 8 to trigger apoptosis. 89 McL-1 is an anti-apoptotic protein in the Bcl-2 family proteins, which is essential for the survival of normal cells. It is overexpressed in various cancers, such as lung cancer, colon cancer, multiple myeloma, etc., and is closely associated with poor prognosis.…”

Leukemia Inhibitory Factor Receptor Is Involved in Apoptosis in Rat Astrocytes Exposed to Oxygen-Glucose Deprivation

“…Resulting from cell damage caused by several factors, apoptosis is a widely known cell death mechanism that is initiated by the upregulation of apoptotic protein production [27, 30–32]. Researchers have found that increased levels of Bax expression may lead to apoptosis via activation of procaspase-3 [32, 33], whereas others define the pivotal actions of Bcl-2, p-Akt, and p-ERK1/2 on balancing cell survival and death [34, 35]. Suppression of Akt activity within the CNS is linked to post-HI injury-induced neuronal death, demonstrating the importance of the phosphoinositide 3-kinase (PI3K)/Akt pathway as an antiapoptotic mechanism to protect neurons [36].…”