nitrophenols and Stomach-Neoplasms

Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.

Topics: Animals; Antineoplastic Agents; Biomarkers, Pharmacological; Biphenyl Compounds; Camptothecin; Drug Synergism; Graft Survival; Humans; Irinotecan; Mice; Mice, Nude; Mice, SCID; Molecular Targeted Therapy; Nitrophenols; Piperazines; Precision Medicine; Stomach Neoplasms; Sulfonamides; Tumor Burden; Xenograft Model Antitumor Assays

Gastric cancer is the fourth most common cancer in the world. The clinical applications of both chemotherapy and targeted drugs are limited because of the complexity of gastric cancer. In this study, sulforhodamine B, colony formation assay, 4',6-diamidino-2-phenylindole (DAPI) stain, flow cytometry were used to determine the in vitro cytotoxicity, apoptosis and mitochondrial membrane potential of gastric cancer AGS and HGC-27 cells before and after treatment. Real-time PCR and Western blot were used to analyse the mRNA transcription and protein expression respectively. Confocal microscopy was used to determine the localization of target protein within the cells. Treatment with the combination of ABT-737 and 2,5-dimethyl-celecoxib (DMC) showed strong synergistic effect in both AGS and HGC-27 cells. Moreover, DMC would not influence the intracellular prostaglandin E2 (PGE2) level, thus lacking the toxicity profile of celecoxib. Interestingly, given the significant synergistic effect, combination treatment did not affect the protein expression of BH-3 proteins including Puma, Noxa and Bim. In combination treatment, cell apoptosis was found independent of caspase-3 activation. The translocation of apoptosis-inducing factor (AIF) from mitochondrion to nuclear was responsible for the induced apoptosis in the combination treatment. Taken together, this study provided a novel combination treatment regimen for gastric cancer. Furthermore, the existence of caspase-independent apoptotic pathway induced by treatment of ABT-737 was not yet seen until combined with DMC, which shed light on an alternative mechanism involved in Bcl-2 inhibitor-induced apoptosis.

Topics: Apoptosis; Apoptosis Inducing Factor; Biphenyl Compounds; Celecoxib; Cell Line, Tumor; Cell Lineage; Cell Nucleus; Drug Synergism; Endoplasmic Reticulum Stress; Humans; Membrane Potential, Mitochondrial; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Protein Transport; Pyrazoles; Stomach Neoplasms; Sulfonamides

Phospho-nonsteroidal anti-inflammatory drugs (phospho-NSAIDs) are novel NSAID derivatives with improved anticancer activity and reduced side effects in preclinical models. Here, we studied the metabolism of phospho-NSAIDs by carboxylesterases and assessed the impact of carboxylesterases on the anticancer activity of phospho-NSAIDs in vitro and in vivo. The expression of human liver carboxylesterase (CES1) and intestinal carboxylesterase (CES2) in human embryonic kidney 293 cells resulted in the rapid intracellular hydrolysis of phospho-NSAIDs. Kinetic analysis revealed that CES1 is more active in the hydrolysis of phospho-sulindac, phospho-ibuprofen, phospho-naproxen, phospho-indomethacin, and phospho-tyrosol-indomethacin that possessed a bulky acyl moiety, whereas the phospho-aspirins are preferentially hydrolyzed by CES2. Carboxylesterase expression leads to a significant attenuation of the in vitro cytotoxicity of phospho-NSAIDs, suggesting that the integrity of the drug is critical for anticancer activity. Benzil and bis-p-nitrophenyl phosphate (BNPP), two carboxylesterase inhibitors, abrogated the effect of carboxylesterases and resensitized carboxylesterase-expressing cells to the potent cytotoxic effects of phospho-NSAIDs. In mice, coadministration of phospho-sulindac and BNPP partially protected the former from esterase-mediated hydrolysis, and this combination more effectively inhibited the growth of AGS human gastric xenografts in nude mice (57%) compared with phospho-sulindac alone (28%) (p = 0.037). Our results show that carboxylesterase mediates that metabolic inactivation of phospho-NSAIDs, and the inhibition of carboxylesterases improves the efficacy of phospho-NSAIDs in vitro and in vivo.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Carboxylesterase; Carboxylic Ester Hydrolases; Cell Line, Tumor; Cell Survival; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; HEK293 Cells; Humans; Hydrolysis; Ibuprofen; Indomethacin; Inhibitory Concentration 50; Kinetics; Mice; Mice, Inbred BALB C; Mice, Nude; Naproxen; Nitrophenols; Organophosphates; Organophosphorus Compounds; Phenylglyoxal; Stomach Neoplasms; Sulindac; Transfection; Valproic Acid; Xenograft Model Antitumor Assays

This study investigated the potential synergistic effects of two inducers of apoptosis: the small molecule ABT-737 and arsenic trioxide (ATO).. Human gastric carcinoma cell lines SGC-7901 and MGC-803 were used to determine the effects of ABT-737 and ATO (alone or in combination) on cell proliferation and apoptosis in vitro. In vivo effects of these drugs were investigated in SGC-7901 solid tumours, grown in immunodeficient mice.. ABT-737 and ATO inhibited proliferation and induced apoptosis in SGC-7901 and MGC-803 cells in concentration- and time-dependent manners, and showed a synergistic effect. ABT-737 disturbed the binding of B cell lymphoma (Bcl)-2 homologous antagonist killer and Bcl-extra large; ATO downregulated myeloid cell leukaemia (Mcl)-1 protein and upregulated Mcl-1short, the short splicing variant. ABT-737 and ATO significantly suppressed SGC-7901 xenograft growth, synergistically inhibited tumour growth and induced apoptosis in vivo.. This study provides preclinical evidence that ABT-737 and ATO synergize to induce apoptosis of gastric carcinoma cells, suggesting that further investigation of these agents (as potential treatments for gastric cancer) is warranted.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Arsenic Trioxide; Arsenicals; Biphenyl Compounds; Carcinoma; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nitrophenols; Oxides; Piperazines; Stomach Neoplasms; Sulfonamides; Tumor Burden; Xenograft Model Antitumor Assays