ABSTRACT
BACKGROUND: Solitary hamartomatous polyps (SHPs) are rare lesions. Endoscopic full-thickness resection (EFTR) is a highly efficient and minimally invasive endoscopic procedure that benefits from complete lesion removal and high safety. CASE SUMMARY: A 47-year-old man was admitted to our hospital after experiencing hypogastric pain and constipation for over fifteen days. Computed tomography and endoscopy revealed a giant pedunculated polyp (approximately 18 cm long) in the descending and sigmoid colon. This is the largest SHP reported to date. Having considered the condition of the patient and mass growth, the polyp was removed using EFTR. CONCLUSION: On the basis of clinical and pathological evaluations, the mass was considered an SHP.
ABSTRACT
Two new cyclometalated Ru(II)-ß-carboline complexes, [Ru(dmb)2(Cl-Ph-ßC)](PF6) (dmb = 4,4'-dimethyl-2,2'-bipyridine; Cl-Ph-ßC = Cl-phenyl-9H-pyrido[3,4-b]indole; RußC-3) and [Ru(bpy)2(Cl-Ph-ßC)](PF6) (bpy = 2,2'-bipyridine; RußC-4) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC50 values of 3.2 ± 0.4 µM (RußC-3) and 4.1 ± 0.6 µM (RußC-4), which were considerably lower than that of non-cyclometalated Ru(II)-ß-carboline complex [Ru(bpy)2(1-Py-ßC)] (PF6)2 (61.2 ± 3.9 µM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RußC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RußC-3-induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RußC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs.
Subject(s)
Antineoplastic Agents , Ruthenium , Uterine Cervical Neoplasms , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Carbolines/pharmacology , Cell Cycle Checkpoints , Cell Line, Tumor , Female , HeLa Cells , Humans , Proto-Oncogene Proteins c-akt , Reactive Oxygen Species , Ruthenium/pharmacology , Signal Transduction , Uterine Cervical Neoplasms/drug therapy , ZebrafishABSTRACT
Ruthenium-based complexes have been regarded as one of the most potential metal-based candidates for anticancer therapy. Herein, two ruthenium (II) methylimidazole complexes [Ru(MeIm)4(4npip)]2+ (complex 1) and [Ru(MeIm)4(4mopip)]2+ (complex 2) were synthesized and evaluated for their in vitro anticancer activities. The results showed that these ruthenium (II) methylimidazole complexes exhibited moderate antitumor activity comparable with cisplatin against A549, NCI-H460, MCF-7 and HepG2 human cancer cells, but with less toxicity to a human normal cell line HBE. Intracellular distribution studies suggested that complex 2 selectively localized in the mitochondria. Mechanism studies indicated that complex 2 caused cell cycle arrest at G0/G1 phase by regulating cell cycle relative proteins and induced apoptosis through intrinsic pathway, which involved mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage. Further, studies by western blotting suggested that MAPK and AKT signaling pathways were involved in complex 2-induced apoptosis, and they were regulated by the level of ROS. Overall, these findings suggested that complex 2 could be a candidate for further evaluation as a chemotherapeutic agent in the treatment of cancers.
Subject(s)
Apoptosis/drug effects , Ruthenium Compounds/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line , Cell Line, Tumor , DNA Damage , G1 Phase/drug effects , Humans , MAP Kinase Signaling System , Membrane Potential, Mitochondrial/drug effects , Proton Magnetic Resonance Spectroscopy , Reactive Oxygen Species/metabolism , Resting Phase, Cell Cycle/drug effects , Ruthenium Compounds/chemistry , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, UltravioletABSTRACT
Two new cyclometalated Ru(II) complexes of the general formula [Ru(N-N)2(1-Ph-ßC)](PF6), where N-N = 4,4'-dimethyl-2,2'-bipyridine (dmb, Ru1), 2,2'-bipyridine (bpy, Ru2), and 1-Ph-ßC (1-phenyl-9H-pyrido[3,4-b]indole) is a ß-carboline alkaloids derivatives, have been synthesized and characterized. The in vitro cytotoxicities, cellular uptake and localization, cell cycle arrest and apoptosis-inducing mechanisms of these complexes have been extensively explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, inductively coupled plasma mass spectrometry (ICP-MS), flow cytometry, comet assay, inverted fluorescence microscope as well as western blotting experimental techniques. Notably, Ru1 and Ru2 exhibit potent antiproliferative activities against selected human cancer cell lines with IC50 values lower than those of cisplatin and other non-cyclometalated Ru(II) ß-carboline complexes. The cellular uptake and localization exhibit that these complexes can accumulate in the cell nuclei. Further antitumor mechanism studies show that Ru1 and Ru2 can cause cell cycle arrest in the G0/G1 phase by regulating cell cycle relative proteins and induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carbolines/pharmacology , Organometallic Compounds/pharmacology , Ruthenium/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carbolines/chemistry , Cell Cycle Checkpoints/drug effects , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Ruthenium/chemistry , Structure-Activity RelationshipABSTRACT
In the present study, it was found that the ruthenium (II) imidazole complex [Ru(Im)4(dppz)]2+ (Ru1) could induce significant growth inhibition and apoptosis in A549 and NCI-H460 cells. Apart from the induction of apoptosis, it was reported for the first time that Ru1 induced an autophagic response in A549 and NCI-H460 cells as evidenced by the formation of autophagosomes, acidic vesicular organelles (AVOs), and the up-regulation of LC3-II. Furthermore, scavenging of reactive oxygen species (ROS) by antioxidant NAC or Tiron inhibited the release of cytochrome c, caspase-3 activity, and eventually rescued cancer cells from Ru1-mediated apoptosis, suggesting that Ru1 inducing apoptosis was partially caspase 3-dependent by triggering ROS-mediated mitochondrial dysfunction in A549 and NCI-H460 cells. Further study indicated that the extracellular signal-regulated kinase (ERK) signaling pathway was involved in Ru1-induced autophagy in A549 and NCI-H460 cells. Moreover, blocking autophagy using pharmacological inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhanced Ru1-induced apoptosis, indicating the cytoprotective role of autophagy in Ru1-treated A549 and NCI-H460 cells. Finally, the in vivo mice bearing A549 xenografts, Ru1 dosed at 10 or 20 mg/kg significantly inhibited tumor growth.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Imidazoles/pharmacology , Lung Neoplasms/drug therapy , Mitochondria/drug effects , Organometallic Compounds/pharmacology , Ruthenium/pharmacology , A549 Cells , Animals , Autophagosomes/drug effects , Autophagosomes/metabolism , Autophagosomes/pathology , Caspase 3/metabolism , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Cytochromes c/metabolism , Dose-Response Relationship, Drug , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice, Inbred BALB C , Mice, Nude , Microtubule-Associated Proteins/metabolism , Mitochondria/metabolism , Mitochondria/pathology , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
A new ruthenium methylimidazole complex [Ru(MeIm)4(p-cpip)](2+) (Ru1, p-cpip=2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline, MeIm=1-methylimidazole) has been synthesized and characterized. The cellular uptake, in vitro cytotoxicities, cell cycle arrest and apoptosis-inducing mechanism of this Ru(II) complex have been extensively explored by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, Comet assay, inverted fluorescence microscope as well as Western blotting experimental techniques. Notably, Ru1 displayed relatively high cytotoxic activity against lung cancer A549 cells and had high selectivity between tumor and normal cells in comparison with cisplatin. Further studies showed that Ru1 caused cell cycle arrest at G0/G1 phase and induced apoptosis via the mitochondrial pathway, which involved reactive oxygen species (ROS) accumulation, mitochondrial dysfunction and Bcl-2 and caspase correlative family member activation. For providing more information about the possible antitumor mechanism, the in vitro DNA binding studies have been also investigated by different spectrophotometric methods, thermal denaturation and viscosity measurements.
