Eight new annonaceous acetogenins, squamotin A-D (1-4), annosquatin IV-V (5 and 6), muricin O (7) and squamosten B (8), together with four known ones (9-12) were isolated from the seeds of Annona squamosa. Their structures were elucidated by chemical methods and spectral data. The inhibitory activities of compound 1-9 against three multidrug resistance cell lines were evaluated. All tested compounds showed strong cytotoxicity.
Acetogenins ; chemistry ; isolation & purification ; pharmacology ; toxicity ; Annona ; chemistry ; Antineoplastic Agents, Phytogenic ; chemistry ; isolation & purification ; pharmacology ; toxicity ; Cell Line, Tumor ; Cell Survival ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; Plant Extracts ; chemistry ; pharmacology ; toxicity ; Seeds ; chemistry

The present study carried out a phytochemical investigation of the methanol extract of the branches and leaves of Clausena lansium and afforded nine carbazole alkaloids (compounds 1-9) including two new carbazole alkaloids, claulansiums A and B (compounds 1 and 2). The new compounds were elucidated on the basis of extensive spectroscopic data (MS, NMR, IR, and UV) and the known compounds were identified by comparing spectroscopic data with those reported in literature. All the isolated compounds were tested for their cytotoxic activity against A549 and Hela cancer cell lines. Our results showed that compounds 2-6 exhibited varying degrees of cytotoxicity to cancer cells, with IC values ranging from 8.67 to 98.89 μmol·L.
A549 Cells ; Alkaloids ; chemistry ; isolation & purification ; toxicity ; Antineoplastic Agents ; chemistry ; isolation & purification ; toxicity ; Carbazoles ; chemistry ; isolation & purification ; toxicity ; Cell Line, Tumor ; Cell Survival ; drug effects ; Clausena ; chemistry ; HeLa Cells ; Humans ; Molecular Structure ; Plant Extracts ; chemistry ; toxicity ; Plant Leaves ; chemistry ; Plant Stems ; chemistry ; Plants, Medicinal ; chemistry

Two previously undescribed steroidal compounds, 16, 23-epoxy-22, 26-epimino-cholest-22(N), 23, 25(26)-trien-3β-ol-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside (1) and 26-O-β-D-glucopyranosyl-(25R)-5α-furost-20(22)-en-3β, 26-diol (2), together with 7 known ones including 26-O-β-D-glucopyranosyl-(25R)-5, 20(22)-dien-furost-3β, 26-diol (3), (25R)-5-en-spirost-3β-ol-O-β-D-glucopyranosyl-(1→4)-[α-L-rhmanopyranosyl-(1→2)]-β-D-galactopyranoside (4), funkioside D (5), aspidistrin (6), tigogenin-3-O-β-D-lucotrioside (7), desglucolanatigonin II (8), and degalactotigonin (9), were isolated from Solanum lyratum Thunb. Their cytotoxic activities were tested in two cancer cell lines by MTT method. One of the steroidal glycosides (6) showed significant cytotoxic activity against gastric cancer SGC7901 and liver cancer BEL-7402 cells.
Alkaloids ; chemistry ; isolation & purification ; toxicity ; Antineoplastic Agents ; chemistry ; isolation & purification ; toxicity ; Cell Line, Tumor ; Cell Survival ; drug effects ; Glycosides ; chemistry ; pharmacology ; toxicity ; Humans ; Inhibitory Concentration 50 ; Molecular Structure ; Phytosterols ; chemistry ; isolation & purification ; toxicity ; Plant Extracts ; chemistry ; toxicity ; Plants, Medicinal ; chemistry ; Solanum ; chemistry ; Sterols ; chemistry ; pharmacology ; toxicity

The therapeutic application of deoxypodophyllotoxin (DPT) is limited due to its poor water solubility and stability. In the present study, the micelles assembled by the amphiphilic block copolymers (mPEG-PDLLA) were constructed to improve the solubility and safety of DPT for their in vitro and in vivo application. The central composite design was utilized to develop the optimal formulation composed of 1221.41 mg mPEG-PDLLA, the weight ratio of 1 : 4 (mPEG-PDLLA : DPT), 30 mL hydration volume and the hydration temperature at 40 °C. The results showed that the micelles exhibited uniformly spherical shape with the diameter of 20 nm. The drug-loading and entrapment efficiency of deoxypodophyllotoxin-polymeric micelles (DPT-PM) were about (20 ± 2.84)% and (98 ± 0.79)%, respectively, indicating that the mathematical models predicted well for the results. Compared to the free DPT, the cytotoxicity showed that blank micelles possessed great safety for Hela cells. In addition, the DPT loaded micelle formulation achieved stronger cytotoxicity at the concentration of 1 × 10 mol·L, which showed significant difference from free DPT (P < 0.05). In conclusion, the micelles were highly promising nano-carriers for the anti-tumor therapy with DPT.
Antineoplastic Agents ; chemistry ; toxicity ; Cell Survival ; drug effects ; Drug Carriers ; chemistry ; Drug Delivery Systems ; methods ; Drug Design ; HeLa Cells ; Humans ; Micelles ; Particle Size ; Podophyllotoxin ; analogs & derivatives ; chemistry ; toxicity ; Polyesters ; chemistry ; Polyethylene Glycols ; chemistry ; Solubility ; Surface Properties

The underground cane of Schizocapsa plantaginea (Hance) has long been used by Chinese ethnic minority as a constituent of anti-cancer formulae. Saponins are abundant secondary metabolic products located in the underground cane of this plant. The potential therapeutic effects of total saponins isolated from Schizocapsa plantaginea (Hance) (SSPH) on human hepatocellular carcinoma (HCC) were tested in vitro in human liver cancer cell lines, SMMC-7721 and Bel-7404. Apoptosis and cell cycle arrest were determined using flow cytometry, caspase activation was determined by ELISA, and PARP, cleaved PARP, mitogen-activated protein kinase (MAPK) expression and phosphorylation were measured using Western blotting analysis. In vivo anti-HCC effects of SSPH were verified in nude mouse xenograft model. SSPH exerted markedly inhibitory effect on HCC cell proliferation in time- and concentration-dependent manner. Moreover, SSPH significantly induced apoptosis through caspase-dependent signaling and arrested cell cycle at G/M phase. These anti-proliferation effects of SSPH were associated with up-regulated phosphorylation of extracellular signal-regulated kinase-1/2 (Erk1/2) and c-jun-NH2-kinase-1/2 (JNK1/2) and reduced phosphorylation of p38MAPK. Furthermore, inhibitors of ERK, UO126, and JNK, SP600125 inhibited the anti-proliferation effects by SSPH, suggesting that Erk and JNK were the effector molecules in SSPH induced anti-proliferative action. During in vivo experiments, SSPH was found to inhibit xenograft tumor growth in nude mice, with a similar mechanism in vitro. Our study confirmed that SSPH exerted antagonistic effects on human liver cancer cells both in vitro and in vivo. Molecular mechanisms underlying SSPH action might be closely associated with MAPK signaling pathways. These results indicated that SSPH has potential therapeutic effects on HCC.
Animals ; Antineoplastic Agents ; isolation & purification ; pharmacology ; toxicity ; Apoptosis ; drug effects ; Caspases ; genetics ; metabolism ; Cell Cycle Checkpoints ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Dioscoreaceae ; chemistry ; Heterografts ; drug effects ; growth & development ; Humans ; Inhibitory Concentration 50 ; Liver Neoplasms ; drug therapy ; metabolism ; pathology ; MAP Kinase Signaling System ; drug effects ; Mice ; Mice, Nude ; Phosphorylation ; drug effects ; Plant Tubers ; chemistry ; Poly (ADP-Ribose) Polymerase-1 ; metabolism ; Saponins ; isolation & purification ; pharmacology ; toxicity

Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. Our previous study has shown that icariin could reverse MDR in MG-63 doxorubicin-resistant (MG-63/DOX) cells. It is reported that icariin is usually metabolized to icariside II and icaritin. Herein, we investigated the effects of icariin, icariside II, and icaritin (ICT) on reversing MDR in MG-63/DOX cells. Among these compounds, ICT exhibited strongest effect and showed no obvious cytotoxicity effect on both MG-63 and MG-63/DOX cells ranging from 1 to 10 μmol·L. Furthermore, ICT increased accumulation of rhodamine 123 and 6-carboxyfluorescein diacetate and enhanced DOX-induced apoptosis in MG-63/DOX cells in a dose-dependent manner. Further studies demonstrated that ICT decreased the mRNA and protein levels of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1). We also verified that blockade of STAT3 phosphorylation was involved in the reversal effect of multidrug resistance in MG-63/DOX cells. Taken together, these results indicated that ICT may be a potential candidate in chemotherapy for osteosarcoma.
ATP Binding Cassette Transporter, Subfamily B ; drug effects ; genetics ; metabolism ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Survival ; drug effects ; Dose-Response Relationship, Drug ; Doxorubicin ; metabolism ; pharmacology ; toxicity ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Flavonoids ; pharmacology ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Multidrug Resistance-Associated Proteins ; drug effects ; genetics ; metabolism ; Osteosarcoma ; drug therapy ; metabolism ; pathology ; Phosphorylation ; drug effects ; Rhodamine 123 ; metabolism ; STAT3 Transcription Factor ; antagonists & inhibitors ; metabolism ; Triterpenes ; pharmacology

Autophagy is a crucial biological process in eukaryotes, which is involved in cell growth, survival and energy metabolism. It has been confirmed that autophagy mediates toxicity of anticancer drugs, especially in heart, liver and neuron. It is important to understand the function and mechanism of autophagy in anticancer drugs-induced toxicity. Given that autophagy is a double-edged sword in the maintenance of the function of heart, liver and neuron, the autophagy-mediated toxicity are very complicated in the body. We provide a review on the concept of autophagy and current status about autophagy-mediated toxicity of anticancer drugs. The knowledge is crucial in the basic study of anticancer drugs-induced toxicity, and provides some strategies for the development of alleviating the toxicity of anticancer drugs.
Antineoplastic Agents ; pharmacology ; toxicity ; Autophagy ; Humans ; Neoplasms ; drug therapy

To investigate the function and regulation mechanism of ATP-binding cassette, subfamily G, member 2 (ABCG2) in retinoblastoma cancer stem cells (RCSCs), a long-term culture of RCSCs from WERI-Rb1 cell line was successfully established based on the high expression level of ABCG2 on the surface of RCSCs. To further explore the molecular mechanism of ABCG2 on RCSCs, a microRNA that specifically targets ABCG2 was predicted. Subsequently, miR-3163 was selected and confirmed as the ABCG2-regulating microRNA. Overexpression of miR-3163 led to a significant decrease in ABCG2 expression. Additionally, ABCG2 loss-of-function induced anti-proliferation and apoptosis-promoting functions in RCSCs, and multidrug resistance to cisplatin, carboplatin, vincristine, doxorubicin, and etoposide was greatly improved in these cells. Our data suggest that miR-3163 has a significant impact on ABCG2 expression and can influence proliferation, apoptosis, and drug resistance in RCSCs. This work may provide new therapeutic targets for retinoblastoma.
3' Untranslated Regions ; ATP Binding Cassette Transporter, Sub-Family G, Member 2/antagonists & inhibitors/genetics/*metabolism ; Antagomirs/metabolism ; Antineoplastic Agents/toxicity ; Apoptosis/drug effects ; Base Sequence ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/drug effects ; Gene Silencing ; Humans ; MicroRNAs/antagonists & inhibitors/genetics/*metabolism ; Neoplasm Proteins/antagonists & inhibitors/genetics/*metabolism ; Neoplastic Stem Cells/*metabolism ; Retinoblastoma/metabolism/pathology ; Sequence Alignment ; Transfection

Drug therapy is essential for cancer treatment. The molecular targeted anticancer drugs develop rapidly in recent years, since the effectiveness of traditional chemotherapy is unsatisfactory and the adverse reactions are high. However, molecular targeted anticancer drugs would damage the function of heart, liver or lung, and may cause adverse effects such as hand-foot syndrome, which restrains their clinical application. Therefore, it is critical for pharmaceutical toxicology to study the toxicity, the related mechanisms and the preventive measures of molecular targeted anticancer drugs.
Antineoplastic Agents ; toxicity ; Humans ; Molecular Targeted Therapy

OBJECTIVETo investigate the effects of total flavonoids of Litsea Coreana (TFLC) on the gap junction (GJ) intercellular communication in TM3 testicular Leydig cells and whether TFLC can reduce the cytotoxicity of oxaliplatin (OHP) in vitro.

METHODSWe detected the effect of TFLC on the dye spread of the in vitro cultured TM3 cells by parachute assay, observed changes in the expression of connexin 43 (Cx43) total protein in the TFLC-treated TM3 cells by Western blot, and determined the effects of TFLC on the expression of Cx43 on the membrane of the TM3 cells by immunofluorescence assay and on the cytotoxicity of OHP by MTT assay.

RESULTSTFLC obviously enhanced the GJ function with the increasing of the TFLC concentration in the TM3 cells. Western blot and immunofluorescence assay confirmed that TFLC significantly enhanced the expression of Cx43 total protein and Cx43 expression on the membrane of the TM3 cells. MTT assay showed that at a high cell density (confluent with GJ formation), 20 microg/ml TFLC enhanced the GJ function of the TM3 cells and reduced the cytotoxicity of OHP (P < 0.05), while at a low density (preconfluent with no GJ formation), TFLC exhibited no effect on the cytotoxicity of OHP (P > 0.05).

CONCLUSIONTFLC increases the Cx43 expression and GJ function in normal TM3 Leydig cells, and the enhancement of GJ function reduces the cytotoxicity of OHP.

Antineoplastic Agents ; toxicity ; Cell Communication ; drug effects ; physiology ; Cell Count ; Connexin 43 ; metabolism ; Flavonoids ; pharmacology ; Gap Junctions ; drug effects ; Humans ; In Vitro Techniques ; Leydig Cells ; drug effects ; ultrastructure ; Litsea ; chemistry ; Male ; Organoplatinum Compounds ; antagonists & inhibitors ; toxicity ; Proteins ; metabolism