Teroxirone as an anticancer agent is used to treat human lung cancer by inducing apoptotic cell death. Previous studies have demonstrated that the status of the tumor suppressor p53 determined the onset of apoptotic cell death in human non-small cell lung cancer cells (NSCLC). In order to further understand the underlying mechanisms of lung cancer, the present study explored the targets of teroxirone. By including antioxidants, the present study analyzed changes in cell proliferation, cell cycle division, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), expression of apoptosis markers and cytochrome c distribution. Subsequent to a 12 h treatment with low concentrations of teroxirone, MMP was suppressed, followed by ROS production and apoptosis in lung cancer cells carrying wild type p53. N-acetylcysteine inhibited apoptotic cell death. The depleted expression of p53, reduction of apoptosis-associated active caspase-3 and poly ADP-ribose polymerase cleavage with resurgence of the pro-survival signal protein kinase B, all demonstrated an antioxidant-mediated reduction of apoptosis by teroxirone. The diminished ROS intensity inhibited the release of mitochondrial cytochrome c and DNA damage. The present study provided evidence that teroxirone treatment induced the ROS-activated intrinsic apoptotic pathway, which led to cell death in human NSCLC cells.

As a practical and safe herbal medicine, the seeds of Brucea javanica (L.) Merr., were used to cure patients suffering from infectious diseases such as malaria. Recent advances revealed that the herb could also be a useful cancer therapy agent. The study demonstrated that aqueous B. javanica (BJ) extract attenuated the growth of human non-small-lung cancer cells bearing mutant L858R/T790M epidermal growth factor receptor (EGFR). The reduced cell viability in H1975 cells was attributed to apoptosis. Transfection of EGFR small hairpin RNA reverted the sensitivities. When nude mice were fed BJ extract, the growth of xenograft tumors, as established by H1975 cells, was suppressed. Additional histological examination and fluorescence analysis of the resected tissues proved that the induced apoptosis mitigated tumor growth. The work proved that the BJ extract exerted its effectiveness by targeting lung cancer cells carrying mutated EGFR while alleviating tumorigenesis. Aqueous BJ extract is a good candidate to overcome drug resistance in patients undergoing target therapy.

Numerous approaches suggested that compounds with conjugated triazole moieties or benzoxazone pharmacores are effective to antagonize proliferation of human tumors. The current study reported that a synthetic triazole-conjugated benzoxazone, 4-((5-benzyl-1H-1,2,3-triazol-3-yl)-methyl)-7-methoxy-2H-benzo[b][1,4]-oxazin-3(4H)-one (BTO), inhibited growth rates of human non-small cell lung cancer cells. The cytotoxicity can be enhanced with increasing drug concentrations. More evidence supported that the induced reactive oxygen species lead to ultimate apoptotic cell death by recruiting autophagy. The mechanistic pathway as elucidated involved tumor suppressor p53 activation and LC3-1 conversion followed by PARP and procaspase-3 cleavage. Autophagy inhibition reverted apoptotic death and restored cell viabilities. BTO suppressed the development of A549 cell xenograft tumors by activating autophagy and apoptosis simultaneously. As an efficient tumor growth inhibitor with relatively small molecular weight, BTO is a viable addition to the existing list of lung cancer treatment.

Protein phosphatase 2A is one of four major classes of serine/threonine phosphatases. Overexpression of brain-specific regulatory subunit PPP2R2 in neuron cells is implicated in pathogenesis. The alternative splicing of PPP2R2B encodes two isoforms. They are subunit of cytoplasmic specific Bβ1 and mitochondria-targeted Bβ2. The two constructs were transfected into human neuroblastoma cells, SK-N-SH, respectively, and the stable clones overexpressing either Bβ1 or Bβ2 established. We have reported that Bβ2 clones are sensitive to reactive oxygen species (ROS) treatment by inducing autophagic cell death. To study more on the onset of neuropathogenesis under strain, both clones were exposed to different environmental stress, e.g. starvation and endoplasmic reticulum (ER) stress. To learn how PPP2R2B overexpression responds to starvation, cells were incubated in Hank's buffered salt solution of deprived nutrient. Cell death was induced in Bβ1 clones after 6 h starvation, but not in Bβ2 clones. The pharmacological inhibitor, Bafilomycin A1, rescued the cell death while suppressing autophagy. On the other hand, to assess how cells respond to ER stress, the cells were treated with 0.1 μM of N-glycosylation inhibitor, tunicamycin (TM). In contrast with Bβ1, the apoptotic cell death appeared in Bβ2 after 48 h treatment. The formation of autophagolysosome was detected in Bβ2 following 12 h treatment with TM as evidenced by lysotracker and GFP-LC3 staining for fluorescence microscopy analysis. The autophagy inhibitor, 3-methyladenine, salvaged the final apoptosis. The stable cell lines with ectopically transfected PPP2R2B genes encoding isoforms of brain-specific regulatory subunit exhibit distinct apoptosis under different stressors. The induced autophagic apoptotic cell death is related to mitochondrial membrane potential drop and ROS generation. Disturbance of autophagy alleviates the induced cell death. The results promised a good model for understanding the onset in pathogenesis under stress in neuron cells with aberrant PPP2R2B expression.

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