A Novel Naphthalimide Compound Restores p53 Function in Non-small Cell Lung Cancer by Reorganizing the Bak·Bcl-xl Complex and Triggering Transcriptional Regulation.

p53 inactivation is a hallmark in non-small-cell lung cancer (NSCLC). It is therefore highly desirable to develop tumor-specific treatment for NSCLC therapy by restoring p53 function. Herein, a novel naphthalimide compound, NA-17, was identified as a promising drug candidate in view of both its anticancer activity and mechanism of action. NA-17 exhibited strong anticancer activity on a broad range of cancer cell lines but showed low toxicity to normal cell lines, such as HL-7702 and WI-38. Moreover, NA-17 showed p53-dependent inhibition selectivity in different NSCLC cell lines due to the activation state of endogenous p53 in the background level. Further studies revealed that NA-17 caused cell cycle arrest at the G1 phase, changed cell size, and induced apoptosis and cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that targeted accumulation of phospho-p53 in mitochondria and nuclei induced by NA-17 resulted in activation of Bak and direct binding of phospho-p53 to the target DNA sequences, thereby evoking cell apoptosis and cell cycle arrest and eventually leading to irreversible cancer cell inhibition. This work provided new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent naphthalimide compounds.

Palbociclib triggers apoptosis in bladder cancer cells by Cdk2-induced Rad9-mediated reorganization of the Bak.Bcl-xl complex.

Palbociclib is a Cdk4/6 inhibitor approved for metastatic estrogen receptor-positive breast cancer. The drug is also under clinical evaluation for metastatic urothelial cancer and other solid tumors. Preclinical studies from multiple tumor types suggest that other factors also affect the sensitivity of individual tumors to Cdk4/6 inhibitor. We show here that Cdk2 has an essential role in palbociclib antitumor effect against bladder cancers. We found that palbociclib induced apoptosis instead of cell cycle arrest to exhibit its anticancer activity in T24 cells, as was evidenced by membrane blebbing, caspase-3 activation and AIF release from mitochondria. Cdk2 activation was important to palbociclib-induced apoptotic triggering activity, since depletion of Cdk2 significantly inhibited caspase-3 activation and cell apoptosis. Cdk2 activation caused p-Rad9 translocation to the mitochondria and subsequently interaction with Bcl-xl, leading to conformational activation of Bak and cell apoptosis. The anticancer activity and Cdk2 activation of palbociclib-treated mice were finally validated in a T24 xenograft model. Collectively, these results together demonstrate that palbociclib exerts its anticancer effect in T24 cells mainly through Cdk2 activation. Our findings provide new insights into the molecular interactions and anticancer mechanisms of Cdk4/6 inhibitors.

miRNA­328 overexpression confers cisplatin resistance in non­small cell lung cancer via targeting of PTEN.

Chemotherapy resistance, the molecular mechanism of which is complex and has not been fully understood, poses a major challenge in the treatment of patients with non­small cell lung cancer (NSCLC). The dysregulation of microRNAs (miRs) has been reported to serve a pivotal role in the development of cancer and drug resistance. In the present study, reverse transcription­quantitative polymerase chain reaction analysis revealed a significant increase in miR­328 and a significant decrease in phosphatase and tensin homolog (PTEN) mRNA expression levels within tumor tissues from patients with cisplatin­resistant NSCLC compared with those of cisplatin­sensitive NSCLC patients. In addition, there was a negative correlation between PTEN mRNA and the miR­328 expression levels. In addition, higher miR­328 expression levels, and lower PTEN mRNA and protein expression levels, were detected in cisplatin­resistant A549 (A549rCDDP) cells when compared with in their parental cells. A549rCDDP cells demonstrated significantly higher cell viability compared with A549 cells following treatment with all concentrations of cisplatin tested (2, 4, 6 and 8 µM). Additionally, transfection of miR­328 inhibitor significantly increased PTEN mRNA and protein expression levels. Furthermore, the present study predicted and confirmed PTEN, a well­known tumor suppressor, as a direct target of miR­328 in NSCLC cells via the online tool MiRanda and a dual luciferase assay, respectively. Cell viability assay and flow cytometry analysis demonstrated that inhibition of miR­328 also induced cellular apoptosis and decreased cell proliferation in A549rCDDP cells treated with cisplatin. In conclusion, these results suggested that abnormal expression of miR­328 may contribute to cisplatin resistance in NSCLC, and may be considered to be a novel therapeutic target and indicator for the treatment and prognosis of patients with NSCLC treated with cisplatin­based chemotherapy.

Preparation of Rhodium(III) complexes with 2(1H)-quinolinone derivatives and evaluation of their in vitro and in vivo antitumor activity.

A series of 2(1H)-quinolinone derivatives and their rhodium (III) complexes were designed and synthesized. All the rhodium (III) complexes exhibited higher in vitro cytotoxicity for Hep G2, HeLa 229, MGC80-3, and NCI-H460 human tumor cell lines than their ligands and cisplatin, and among them complex 9 was found to be selectively cytotoxic to tumor cells. Further investigation revealed that complex 9 caused cell cycle arrest at the G2/M phase and induced apoptosis, and inhibited the proliferation of Hep G2 cells by impeding the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream enzymes. Complex 9 also up-regulated the proapoptotic proteins Bak, Bax, and Bim, which altogether activated caspase-3/9 to initiate cell apoptosis. Notably, complex 9 effectively inhibited tumor growth in the NCI-H460 xenograft mouse model with less adverse effect than cisplatin.

A ß-carboline derivative-based nickel(ii) complex as a potential antitumor agent: synthesis, characterization, and cytotoxicity.

A novel nickel(ii) complex of 6-methoxy-1-pyridine-ß-carboline (4a) was synthesized and characterized. The cytotoxicities of the complex towards six cancer cell lines, including MGC-803, Hep G2, T24, OS-RC-2, NCI-H460, and SK-OV-3, and human normal liver cell line HL-7702 were investigated. The IC50 values for MGC-803, Hep G2, T24, OS-RC-2, NCI-H460 and SK-OV-3 were generally in the micromolar range (3.77-15.10 µM), lower than those of ligand 4 and cisplatin. Furthermore, 4a (6 µM) significantly induced cell cycle arrest at the S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27. Various experiments showed that 4a induced apoptosis, activated caspase-3, increased the levels of reactive oxygen species (ROS) and enhanced the intracellular [Ca2+]c levels in MGC-803. In addition, the expression of intrinsic apoptotic proteins, including cytochrome c and apaf-1, increased. Further intrinsic apoptosis was triggered via executive molecular caspase-9 and caspase-3. In short, 4a exerted its cytotoxic activity primarily through inducing cell cycle arrest at the S phase and intrinsic apoptosis.