Arene Ru(II) Complexes Acted as Potential KRAS G-Quadruplex DNA Stabilizer Induced DNA Damage Mediated Apoptosis to Inhibit Breast Cancer Progress.

A series of arene Ru(II) complexes, [(η6-MeC6H5)Ru(L)Cl]Cl, (L=o-ClPIP, 1; m-ClPIP, 2 and p-ClPIP, 3) (o-ClPIP=2-(2-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline; m-ClPIP=2-(3-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline; p-ClPIP=2-(4-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline) was synthesized and investigated as a potential apoptosis inducer in chemotherapy. Spectroscopy and molecular docking simulations show that 1 exhibits moderated binding affinity to KRAS G-quadruplex DNA by groove mode. Further, in vitro studies reveal that 1 displays inhibitory activity against MCF-7 growth with IC50 = 3.7 ± 0.2 µM. Flow cytometric analysis, comet assay, and immunofluorescence confirm that 1 can induce the apoptosis of MCF-7 cells and G0/G1 phase arrest through DNA damage. In summary, the prepared arene Ru(II) complexes can be developed as a promising candidate for targeting G-quadruplex structure to induce the apoptosis of breast cancer cells via binding and stabilizing KRAS G-quadruplex conformation on oncogene promoter.

Fast detection, a precise and sensitive diagnostic agent for breast cancer.

BACKGROUND: Breast cancer targeting diagnostic agent with effective imaging ability is important in guiding plan formulation, prediction, and curative effect evaluation of tumors in clinic. A tumor-targeting nanoprobe based on the functional and programmable Liquid-Liquid phase separation of AS1411 promoted by Ru(II) complex RuPEP may develop into a potential phosphorescence probe to detect breast cancer cells, where AS1411 act as a tumor-targeting guidance moiety to distinguish tumor cells from normal cells and RuPEP act as a light-emitting element to highlight breast cancer cells. METHODS: Here we designed and constructed a nanoprobe AS1411@RuPEP, and the physicochemical and biochemical properties were characterized by TEM, AFM and EDS. The breast cancer targeting diagnostic capacity was evaluated by normal/tumor cell co-culture assay, tumor cells targeting tracking in xenograft model and cancerous area selectively distinguishing in human patient tissue. RESULTS: Further studies indicated that the nanoprobe exhibits excellent tumor-targeting imaging ability in vitro and in vivo by effectively recognize the over-expressed nucleolin (NCL) on the breast cancer cells membrane. Intriguingly, we discovered that the selectively enrichment of nanoprobe particles in tumor cells is related to ATP-dependent NCL transport processes that rely on the AS1411 component of nanoprobe to recognize NCL. Furthermore, preferential accumulation of nanoprobe is clearly differentiating the human breast cancer tissue surrounding non-cancerous tissue in histological analysis. CONCLUSION: This study produce a potent nanoprobe can be used as a convenient tool to highlight and distinguish tumor cells in vivo, and indicate the tumorous grading and staging in human breast cancer patient pathological section, which provides an effective way for breast cancer diagnostic imaging by targeting recognize NCL.

Synthesis of Fluorinated Imidazole[4,5f][1,10]phenanthroline Derivatives as Potential Inhibitors of Liver Cancer Cell Proliferation by Inducing Apoptosis via DNA Damage.

Phenanthroline derivatives containing fluorinated imidazole ring are effective anti-neoplastic agents. Herein, a series of four fluorinated imidazole[4,5f][1,10]phenanthroline derivatives were synthesized and investigated as potential inhibitors to fight against the growth of liver cancer cells. The in vitro antitumor activity of targeted compounds have been evaluated by using MTT assay, and results showed that compound 4 (2-(2,3-difluorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) exhibited excellent inhibitory effect against the growth of various tumor cells, particularly for HepG2 cells, with IC50 value of approximately 0.29 µM. This result has been further confirmed by colony formation assay, showing that compound 4 suppressed the proliferation of HepG2 cells. Moreover, cell apoptosis (AO/PI dual staining and flow cytometry) analyses as well as comet assay showed that compound 4 may induce apoptosis of HepG2 cells through triggering DNA damage. Furthermore, the in vivo anti-tumor activity were evaluated on zebrafish bearing HepG2 cells showed that compound 4 can observably block the growth of liver cancer cells. All in together, these compounds, particularly compound 4, may be developed as a potential agent to treat liver cancer in the future.

Tanshinone IIA derivatives induced S-phase arrest through stabilizing c-myc G-quadruplex DNA to regulate ROS-mediated PI3K/Akt/mTOR pathway.

Herein, a derivate from tanshinone IIA, 1,6,6-trimethyl-11-phenyl-7,8,9,10-tetrahydro-6H-furo[2',3':1,2]phenanthro[3,4-d]imidazole (TA25), has been synthesized and investigated as potential inhibitor against the proliferation, migration and invasion of lung cancer cells. MTT assay and cell colony formation assay results showed that TA25 exhibits acceptable inhibitory effect against the proliferation of lung cancer A549 cells, and the value of IC50 was about 17.9 µM. This result was further confirmed by the inhibition of TA25 against the growth of xenograft lung cancer cells on zebrafish bearing tumor (A549 lung cancer cells). The results of wound-healing assay and FITC-gelatin invasion assay displayed that TA25 could inhibit the migration and invasion of lung cancer A549 cells. Moreover, the studies on the binding properties of TA25 interact with c-myc G-quadruplex DNA suggested that TA25 can bind in the G-quarter plane formed from G7, G11, G16 and G20 with c-myc G-quadruplex DNA through π-π stacking. Further study of the potential anti-cancer mechanism indicated that TA25 can induce S-phase arrest in lung cancer A549 cells, and this phenomenon resulted from the promotion of the production of reactive oxygen species and DNA damage in A549 cells under the action of TA25. Further research revealed that TA25 could inhibit the PI3K/Akt/mTOR signal pathway and increase the expression of p53 protein. Overall, TA25 can be developed into a promising inhibitor against the proliferation, migration and invasion of lung cancer cells and has potential clinical application in the near future.

Antitumor component recognition from the Aconiti Lateralis Radix Praeparata and Glycyrrhizae Radix et Rhizoma herb pair extract by chemometrics and mean impact value.

The purpose of this research is to recognize the active antitumor components from the mixed pair extract of Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) and Glycyrrhizae Radix et Rhizoma (Gancao in Chinese) using chemometrics and mean impact value (MIV) methods. Firstly, 30 common components of 31 different samples were analyzed quantitatively and qualitatively by HPLC-UV and UPLC-Q-TOF tandem mass spectrometry, respectively. Meanwhile, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were used to test the inhibition activities of the 31 different samples against HeLa cells. Then a back propagation (BP) neural network, support vector regression (SVR), and two optimization algorithms - genetic algorithm (GA) and particle swarm optimization (PSO) - were applied to construct composition-activity relationship (CAR) models for the Fuzi-Gancao extract. Based on the optimal CAR model, the MIV was introduced to evaluate the contribution of each individual component to the anticancer efficacy of the extract. Results indicated that the SVR-PSO model best depicted the complex relationship between the chemical composition and the inhibition effect of a Fuzi-Gancao extract. The 30 common components were ranked by their absolute MIVs, and the top 8, which corresponded to peaks 17, 25, 22, 13, 23, 28, 5, and 7 in the chromatogram, were tentatively deemed to be the main antitumor components. The integrated strategy shows a novel and efficient approach to understanding the potential contributions of components from complicated herbal medicines, and the identified results suggest certain directions for screening and research into new antitumor drugs.