The common adverse reactions caused by poly (ADP-ribose) polymerase (PARP) inhibitors include hematological toxicity, gastrointestinal toxicity and fatigue. The main prevention and treatment of hematological toxicity include: regular blood tests, referral to hematology department when routine treatment is ineffective, and being alert of myelodysplastic syndrome/acute myeloid leukemia. The key points to deal with gastrointestinal toxicity include: taking medicine at the right time, light diet, appropriate amount of drinking water, timely symptomatic treatment, prevention of expected nausea and vomiting, and so on. For fatigue, full assessment should be completed before treatment because the causes of fatigue are various; the management includes massage therapy, psychosocial interventions and drugs such as methylphenidate and Panax quinquefolius according to the severity. In addition, niraparib and fluzoparib can cause hypertension, hypertensive crisis and palpitation. Blood pressure and heart rate monitoring, timely symptomatic treatment, and multidisciplinary consultation should be taken if necessary. When cough and dyspnea occur, high resolution CT and bronchoscopy should be performed to exclude pneumonia. If necessary, PARP inhibitors should be stopped, and glucocorticoid and antimicrobial therapy should be given. Finally, more attention should be paid to drug interaction management, patient self-management and regular monitoring to minimize the risk and harm of adverse reactions of PARP inhibitors.
Humans ; Poly(ADP-ribose) Polymerase Inhibitors/adverse effects* ; Phthalazines/pharmacology* ; Poly(ADP-ribose) Polymerases ; Fatigue/drug therapy*

OBJECTIVETo explore whether MG-132 could enhance the anti-tumor activity of obatoclax against esophageal cancer cell line CaES-17.

METHODSMTT assay was used to determine the cytotoxicity of obatoclax and MG-132 in CaES-17 cells. The IC(50) of obatoclax and MG-132 were used to determine the molar ratio (1:2.4) of the two drugs for combined treatment of the cells. The concentrations of obatoclax and MG-132 ranged from 1/8 IC(50) to 4 IC(50) after serial dilution, and their combination index (CI) was calculated using CompuSyn software. The expression of ubiquitin and the cleavage of PARP, caspase-9, phospho-histone H3 and phospho-aurora A/B/C in the exposed cells were examined with Western blotting; the cell apoptosis was measured by flow cytometry with Annexin V staining, and the percentage of cells in each cell cycle phase was also determined by flow cytometry.

RESULTSThe CI of obatoclax and MG-132 was 0.296 for a 50% inhibition of Caes-17 cells and was 0.104 for a 95% inhibition. The cells treated with obatoclax or MG-132 alone showed increased expression of ubiquitin and cleavage of PARP and caspase-9. Compared with the cells treated with obatoclax or MG-132 alone, the cells with a combined treatment exhibited significantly increased expression of ubiquitin, cleavage of PARP and caspase-9, and expression of phospho-Histone H3 (P<0.05). The combined treatment of the cells also resulted in significantly increased expression of phospho-Aurora A/B/C compared with obatoclax treatment alone. The cells with the combined treatment showed significantly higher percentages of apoptotic cells and cells in sub-G(1) and G(2)/M phases compared with the cells treated with either of the drugs (P<0.05).

CONCLUSIONObatoclax combined with MG-132 shows a significant synergistic anti-tumor effect against esophageal cancer CaES-17 cells by inducing apoptosis and cell cycle arrest.

Apoptosis ; Caspase 9 ; metabolism ; Cell Cycle Checkpoints ; Cell Line, Tumor ; drug effects ; Esophageal Neoplasms ; pathology ; Histones ; metabolism ; Humans ; Leupeptins ; pharmacology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; metabolism ; Pyrroles ; pharmacology

OBJECTIVETo explore the effect of a new emodin derivative E11 on proliferation and apoptosis of T lymphocytic leukemia cell line Molt-4 and its possible mechanisms.

METHODSMTT method was used to plot cell growth curve. Colony culture assay was performed for studying the effect of emodin derivative E11 on colony-formation of Molt-4. The fluorescent microscopy with DAPI staining was used to examine the cell morphological changes after E11 treatment. DNA fragmentation method was used to detect the inducing effect of emodin derivative E11 on cell apoptosis. Western blot was used to determine the expressions of apoptosis-related proteins including procaspase-9, procaspase-3, PARP and PI3K/AKT, MAPK signalling pathway.

RESULTSEmodin derivative E11 could strongly inhibit the growth of Molt-4 with the IC50 in 48 h at 1.381 ± 0.1552 µmol/L in dose-dependent manner. 0.1 µmol/L of E11 could inhibit cell colony formation. The typrical apopototic morphologic changes of Molt cells treated with E11 could be observed under fluorescence microscope with DAPI staining. DNA apoptotic ladder could be observed by DNA fragmentation.The expressions of procaspase -9, procaspase-3, PARP, p-MAPK, p-AKT, mTOR, p-mTOR, p-P70 and p-4BEP1 were down-regulated, while expressions of MAPK, AKT, 4EBP1 and P70 were not changed remarkably after Molt-4 were treated with E11 for 48 h.

CONCLUSIONE11 can remarkably inhibit the proliferation and induce the apoptosis of Molt-4 cells. The mechanism of apoptosis of Molt-4 cells may be related with the suppression of PI3K/AKT and MAPK signalling pathways.

Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; Down-Regulation ; Emodin ; pharmacology ; Humans ; Leukemia, T-Cell ; pathology ; MAP Kinase Signaling System ; Phosphatidylinositol 3-Kinases ; metabolism ; Poly(ADP-ribose) Polymerases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; TOR Serine-Threonine Kinases ; metabolism

The molecular mechanism of DNA damage induced by hydroquinone (HQ) remains unclear. Poly(ADP-ribose) polymerase-1 (PARP-1) usually works as a DNA damage sensor, and hence, it is possible that PARP-1 is involved in the DNA damage response induced by HQ. In TK6 cells treated with HQ, PARP activity as well as the expression of apoptosis antagonizing transcription factor (AATF), PARP-1, and phosphorylated H2AX (γ-H2AX) were maximum at 0.5 h, 6 h, 3 h, and 3 h, respectively. To explore the detailed mechanisms underlying the prompt DNA repair reaction, the above indicators were investigated in PARP-1-silenced cells. PARP activity and expression of AATF and PARP-1 decreased to 36%, 32%, and 33%, respectively, in the cells; however, γ-H2AX expression increased to 265%. Co-immunoprecipitation (co-IP) assays were employed to determine whether PARP-1 and AATF formed protein complexes. The interaction between these proteins together with the results from IP assays and confocal microscopy indicated that poly(ADP-ribosyl)ation (PARylation) regulated AATF expression. In conclusion, PARP-1 was involved in the DNA damage repair induced by HQ via increasing the accumulation of AATF through PARylation.
Antioxidants ; toxicity ; Apoptosis Regulatory Proteins ; genetics ; metabolism ; Cell Line ; DNA Damage ; drug effects ; Gene Expression Regulation ; drug effects ; Gene Silencing ; Histones ; genetics ; metabolism ; Humans ; Hydroquinones ; toxicity ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; genetics ; metabolism ; Protein Transport ; Repressor Proteins ; genetics ; metabolism

OBJECTIVETo investigate the growth-inhibitory effect of sunitinib malate on human bladder transitional cell carcinoma (TCC) in vitro.

METHODSHuman bladder TCC cell line T24 was cultured and exposed to graded concentrations of sunitinib malate for 72 hours in vitro to determine the sensitivities to drug. Cell viability was measured by MTT assay. Cell apoptotic morphology was observed by fluorescence microscope following DAPI staining. Band expressions of Fas, Fas ligand, poly (ADP-ribose) polymerase (PARP) and β-actin were analyzed by Western blot. Wound healing process of T24 cells exposed to sunitinib malate was assayed.

RESULTSSunitinib malate exerted a concentration-dependent and time-dependent inhibitory effect on the T24 cell lines. Fluorescence microscopy showed that small vacuoles appeared in the nuclei of T24 cells and the vacuoles were bigger with higher drug concentrations. The expressions of Fas ligand and PARP in T24 cells treated with sunitinib malate exhibited a concentration-dependent increase. Moreover sunitinib malate suppressed the wound healing process in a concentration-dependent manner.

CONCLUSIONSunitinib malate exerted marked inhibitory activity against bladder cancer cell line T24.

Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Transitional Cell ; metabolism ; pathology ; Cell Line, Tumor ; Fas Ligand Protein ; metabolism ; Humans ; In Vitro Techniques ; Indoles ; pharmacology ; Poly(ADP-ribose) Polymerases ; metabolism ; Pyrroles ; pharmacology ; Urinary Bladder Neoplasms ; metabolism ; pathology ; Wound Healing ; drug effects ; fas Receptor ; metabolism

OBJECTIVETo evaluate the anti-tumor effect of the combination of suberoylanilide hydroxamic acid(SAHA) with statins(lovastatin or simvastatin) on non-small cell lung carcinoma(NSCLC) cells.

METHODSHuman NSCLC A549 cells were treated with SAHA in combination of lovastatin or simvastatin. The cell growth was analyzed by SRB method, and the apoptosis of A549 cells was assessed by flow cytometer. The expression of cleaved poly-ADP-ribose polymerase(cleaved-PARP) and p21 protein was analyzed by Western-blotting when A549 cells were challenged with 2.5μmol/L SAHA and 5μmol/L lovastatin.

RESULTSLovastatin and simvastatin synergized SAHA in the inhibition of A549 cells. SAHA induced apoptosis was also enhanced by lovastatin. Treatment with 2.5μmol/L SAHA significantly up-regulated the expression of p21 protein in 48 h, while the protein expression was reduced in combined treatment with 5μmol/L lovastatin.

CONCLUSIONStatins can synergize the anti-tumor effect of SAHA in human NSCLC cells through a p21-dependent way.

Antineoplastic Agents ; pharmacology ; Apoptosis ; Carcinoma, Non-Small-Cell Lung ; pathology ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; Humans ; Hydroxamic Acids ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Poly(ADP-ribose) Polymerases ; metabolism

OBJECTIVETo investigate the anticancer effect and its mechanism of SN-38 combined with sorafenib on hepatocellular cancer cell lines HepG-2 and BEL-7402.

METHODSSRB colorimetry was employed to measure the viability of HepG-2 and BEL-7402 cells after the treatment of SN-38 with sorafenib. Propidium iodide flow cytometric assay and DAPI staining were used to evaluate the apoptosis of HCC cells. Western blotting was conducted to detect the expression level of apoptosis-related and DNA damage-related proteins.

RESULTSSRB colorimetry showed the synergistic anticancer activities of SN-38 combined with sorafenib, with a combination index of <0.9. The apoptotic rates of HepG-2 cells in control, 60 nmol/L SN-38, 2.5μmol/L sorafenib and combination groups were 4.25%±2.45%, 28.95%±10.75%, 3.49%±2.49% and 53.19%±11.21%, respectively(P<0.05). Western blotting showed that the combination of these two drugs increased the enzymolysis of PARP, Caspase-8 and Caspase-3, and promoted the expression levels of p53, p21 and γ-H2AX significantly.

CONCLUSIONSN-38 and sorafenib have synergistic anticancer activity on hepatocellular carcinoma cells in vitro with the augmentation of apoptosis.

Apoptosis ; Camptothecin ; analogs & derivatives ; pharmacology ; Carcinoma, Hepatocellular ; pathology ; Caspase 3 ; metabolism ; Caspase 8 ; metabolism ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; Histones ; metabolism ; Humans ; Liver Neoplasms ; pathology ; Niacinamide ; analogs & derivatives ; pharmacology ; Phenylurea Compounds ; pharmacology ; Poly(ADP-ribose) Polymerases ; metabolism ; Tumor Suppressor Protein p53 ; metabolism

The biflavonoid isochamaejasmin is mainly distributed in the root of Stellera chamaejasme L. (Thymelaeaceae) that is used in traditional Chinese medicine (TCM) to treat tumors, tuberculosis, and psoriasis. Herein, isochamaejasmin was found to show similar bioactivity against Bcl-2 family proteins to the reference Bcl-2 ligand (-)-gossypol through 3D similarity search. It selectively bound to Bcl-xl and Mcl-1 with Ki values being 1.93 ± 0.13 μmol·L(-1) and 9.98 ± 0.21 μmol·L(-1), respectively. In addition, isochamaejasmin showed slight growth inhibitory activity against HL-60 with IC50 value being 50.40 ± 1.21 μmol·L(-1) and moderate growth inhibitory activity against K562 cells with IC50 value being 24.51 ± 1.62 μmol·L(-1). Furthermore, isochamaejasmin induced apoptosis of K562 cells by increasing the intracellular expression levels of proteins of the cleavage of caspase-9, caspase-3, and PARP which involved in the Bcl-2-induced apoptosis pathway. These results indicated that isochamaejasmin induces apoptosis in leukemia cells by inhibiting the activity of Bcl-2 family proteins, providing evidence for further studying the underlying anti-cancer mechanism of S. chamaejasme L.
Antineoplastic Agents, Phytogenic ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Biflavonoids ; pharmacology ; therapeutic use ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Gossypol ; pharmacology ; HL-60 Cells ; Humans ; Inhibitory Concentration 50 ; K562 Cells ; Leukemia ; drug therapy ; metabolism ; Myeloid Cell Leukemia Sequence 1 Protein ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Poly(ADP-ribose) Polymerases ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; antagonists & inhibitors ; metabolism ; Signal Transduction ; Thymelaeaceae ; chemistry ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo investigate the impact of ethanol extracts from Sedum sarmentosum (ESB) on STAT-3 signaling and its probable molecular mechanism in inducing apoptosis.

METHODMTT assay was used to detect the impact of ESB on HepG2 cell proliferation. FITC-Annexin V-FITC /PI double-labeling were used to investigate the impact on hepatoma carcinoma cell apoptosis. Western blot analysis was used to test the expression levels of cell apoptosis-related proteins Caspase-3, Caspase-9, PARP, P-STAT-3 (Tyr705) , STAT-3, Bcl-2, Mcl-1.

RESULTESB could notably inhibit proliferation of HepG2 cells, and induce HepG2 cell apoptosis, with the dose-dependent inhibitory effect. In addition, ESB could inhibit STAT-3 signaling, down-regulate Mcl-1 and Bcl-2 expressions, and induce degradation/activation of apoptosis-related proteins Caspase-3 and Caspase-9 and PARP degradation in a dose-dependent manner.

CONCLUSIONESB inhibits HepG2 cell proliferation and induces apoptosis by inhibiting STAT-3 signaling and Mcl-1 and Bcl-2 expressions.

Apoptosis ; drug effects ; Blotting, Western ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Ethanol ; chemistry ; Flow Cytometry ; Hep G2 Cells ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein ; metabolism ; Plant Extracts ; chemistry ; pharmacology ; Poly(ADP-ribose) Polymerases ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; STAT3 Transcription Factor ; metabolism ; Sedum ; chemistry ; Signal Transduction ; drug effects ; Time Factors

To investigate the cell proliferation inhibition and apoptosis induced by berberine a-hydroxy f-decanoylethyl sulfonate (HB) on MDA-MB-231 cells in vitro, and the inhibitory effect of HB on the expression of poly adenosine diphosphate RNA polymerase (PARP), MTT assay was used to detect the viability of MDA-MB-231 cells and cell cycle was examined by flow cytometry. The results showed that HB could significantly inhibit the proliferation of MDA-MB-231 cells, and mildly arrested cell cycle progression at S phase. The IC50S for 24, 48 and 72 h treatment were 4.65, 1.46 and 0.75 mg.L-1 (7.55, 2.37 and 1.22 micromol.L-1), respectively. Annexin V-FITC/PI double staining assay showed that HB increased apoptotic ratio of MDA-MB-231 cells. Western blotting analysis showed the expressions of procaspase-3, procaspase-9 and PARP were decreased after HB treatment, while their fragment increased. The results suggest that HB can inhibit the growth and induce apoptosis of MDA-MB-231 cells, which may be associated with inhibition of the expression of procaspase-3, procaspase-9 and PARP.
Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Berberine ; analogs & derivatives ; pharmacology ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Female ; Humans ; Inhibitory Concentration 50 ; Poly(ADP-ribose) Polymerases ; metabolism ; Triple Negative Breast Neoplasms ; metabolism ; pathology