Synthetic Smac Peptide Enhances Chemo-sensitivity of Bladder Cancer Cells

The effects of synthetic Smac peptide （SmacN7） on chemotherapeutic sensitivity of bladder cancer cells were investigated. SmacN7 penetratin peptide was synthesized and delivered into T24 cells. MTT assay was used to evaluate the viability of T24 cells induced by low-dosage of MMC Flow cytometry was used to analyze the proportions of apoptosis. Western blot was used to detect the expression of XIAP and Caspase-3. The activity of Caspase-3 was measured and the effect of SmacN7 combined with MMC on T24 cell lines was also determined. The results showed that SmacN7 penetratin peptide could successfully interact with endogenous XIAP, increase the proportions of apoptosis of T24 cell lines induced by low-dosage of MMC in a dose-and time-dependent manner. An obvious down-regulation of XIAP expression and up-regulation of Caspase-3 was identi-fied by Western blot. The activity of Caspase-3 in experimental group was significantly increased as compared with that in the control group. As compared with MMC group, the viability of T24 cells in SmacN7 penetratin peptide＋MMC group was markedly decreased to 2.22 and 3.61 folds at 24 h and 48 h respectively. It was concluded that SmacN7 penetratin peptide could act as a cell-permeable IAP inhibitor, inhibit the proliferation, induce apoptosis and enhance the chemo-sensitivity of bladder cancer cells to MMC. These findings indicate that SmacN7 penetratin peptide may be a very promising ageut for bladder cancer treatment when used in combination with chemotherapy.

Targeting PP2A for cancer therapeutic modulation

Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.

Anti-cancer effects of sitagliptin,vildagliptin,and exendin-4 on triple-negative breast cancer cells via mitochondrial modulation

Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis,but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line.We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase(AMPK),which activates the downstream transcription factors PGC-1α,PGC-1β,or FOXO1 for mitochondrial biogenesis;above-mentioned incretin-based therapies are also known to activate AMPK.This study evaluated the effects of sitagliptin,vildagliptin,and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis,were examined.Treatment with sitagliptin(100μM),vildagliptin(100μM),and exendin-4(10 nM)for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay,cell migration by scratch,and transwell migration assays,accompanied with marginal reduction in cell numbers along with the apoptotic appearance,the rate of apoptosis,and decreased lactate content in conditioned medium.These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio,increased MitoTracker green and red staining,and increased expression of transcription factors PGC-1α,NRF-1,NRF-2,TFAM,and HO-1.Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1μM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay.Thus,sitagliptin,vildagliptin,and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect.Therapeutic response was in the order of:sitagliptin>vildagliptin>exendin-4.

Salmonella-mediated blood-brain barrier penetration,tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

Chemotherapy is an important adjuvant treatment of glioma,while the efficacy is far from satisfactory,due not only to the biological barriers of blood-brain barrier(BBB)and blood-tumor barrier(BTB)but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as upregulation of P-glycoprotein(P-gp).To address these limitations,we report a bacteria-based drug delivery strategy for BBB/BTB transportation,glioma targeting,and chemo-sensitization.Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment,including macrophages repolarization and neutrophils infiltration.Specifically,tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin(DOX)-loaded bacterial outer membrane vesicles(OMVs/DOX).By virtue of the surface pathogen-associated molecular patterns derived from native bacteria,OMVs/DOX could be selectively recognized by neutrophils,thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect.Moreover,the P-gp expression on tumor cells was silenced by bacteria typeⅢsecretion effector to sensitize the efficacy of DOX,resulting in complete tumor eradication with 100%survival of all treated mice.In addition,the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk,and cardiotoxicity of DOX was also avoided,achieving excellent compatibility.This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.