ABSTRACT
Platinum(II) coordination compounds are widely applied in clinics as anticancer drugs. In this review, we provide a summary of the reports on cytotoxic properties of platinum(II) complexes of selenium donor ligands along with a brief description of their structural features. It has been observed that the platinum(II) complexes of selenones and selenoethers display reasonable antitumor properties and in some cases their cytotoxic activity is greater than cisplatin. The complexes containing NH3 ligands along with selenones were found to exhibit better cytotoxicity compared to the binary Pt-selenone complexes. The mechanistic insights showed that these complexes exert antitumor activity through reactive oxygen species (ROS) generation and induction of apoptosis. The platinum-selenoether coordination compounds can self-assemble into spherical aggregates capable of self-delivery. The self-assembled Pt-selenium aggregates induce cell apoptosis via ROS, which leads to high selectivity between cancer cells and normal cells in cytotoxicity assays.
Subject(s)
Antineoplastic Agents , Selenium , Platinum/pharmacology , Platinum/chemistry , Selenium/pharmacology , Ligands , Reactive Oxygen Species , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistryABSTRACT
The development in the area of novel anticancer prodrugs (conjugates and complexes) has attracted growing attention from many research groups. The dangerous side effects of currently used anticancer drugs, including cisplatin and other platinum based drugs, as well their systemic toxicity is a driving force for intensive search and presents a safer way in delivery platform of active molecules. Silicon based nanocarriers play an important role in achieving the goal of synthesis of the more effective prodrugs. It is worth to underline that silicon based platform including silica and silsesquioxane nanocarriers offers higher stability, biocompatibility of such the materials and pro-longed release of active platinum drugs. Silicon nanomaterials themselves are well-known for improving drug delivery, being themselves non-toxic, and versatile, and tailored surface chemistry. This review summarizes the current state-of-the-art within constructs of silicon-containing nano-carriers conjugated and complexed with platinum based drugs. Contrary to a number of other reviews, it stresses the role of nano-chemistry as a primary tool in the development of novel prodrugs.
Subject(s)
Antineoplastic Agents/chemistry , Drug Carriers/chemistry , Organoplatinum Compounds/chemistry , Silicon/chemistry , Theranostic Nanomedicine , Animals , Antineoplastic Agents/pharmacology , Cisplatin/chemistry , Cisplatin/pharmacology , Drug Delivery Systems , Drug Evaluation, Preclinical , Humans , Molecular Structure , Organoplatinum Compounds/pharmacology , Silicon Dioxide/chemistry , Structure-Activity Relationship , Theranostic Nanomedicine/methodsABSTRACT
FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life.
Subject(s)
Colorectal Neoplasms/drug therapy , Drug Therapy , Leucovorin/therapeutic use , Medicine, Kampo , Organoplatinum Compounds/pharmacology , Adenocarcinoma/drug therapy , Aged , Bevacizumab/therapeutic use , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/pathology , Drug Therapy/methods , Fluorouracil/therapeutic use , Humans , Japan , Male , Medicine, Kampo/methods , Quality of LifeABSTRACT
A chemo-anti-inflammatory strategy is of interest for the treatment of aggressive cancers. The platinum (IV) prodrug with non-steroidal anti-inflammatory drugs (NSAIDs) as axial ligands is designed to efficiently enter tumor cells due to high lipophilicity and release the cytotoxic metabolite and NSAID intracellularly, thereby reducing side effects and increasing the therapeutic efficacy of platinum chemotherapy. Over the last 7 years, a number of publications have been devoted to the design of such Pt(IV) prodrugs in combination with anti-inflammatory chemotherapy, with high therapeutic efficacy in vitro and In vivo. In this review, we summarize the studies devoted to the development of Pt(IV) prodrugs with NSAIDs as axial ligands, the study of the mechanism of their cytotoxic action and anti-inflammatory activity, the structure-activity ratio, and therapeutic efficacy.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Prodrugs , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Ligands , Structure-Activity RelationshipABSTRACT
Evasion of apoptosis is associated with treatment resistance and metastasis in colorectal cancer (CRC). Various cellular processes are associated with evasion of apoptosis. These include overexpression of pro-apoptotic proteins (including p53 and PD-L1), anti-apoptotic proteins (BIRC7/Livin and Bcl-2), chemokine receptors (including DARC), and dysregulation of DNA mismatch repair proteins (including MSH2 and PMS2). The aim of this study was to determine the effect of folinic acid, 5-FU and oxaliplatin (FOLFOX) as a single agent and aspirin plus FOLFOX in various combinations on the aforementioned proteins in human CRC, SW480 cell line and rat models of N-Methyl-N-Nitrosourea (NMU)-induced CRC. In addition, effects of the NMU-induced CRC and chemotherapeutic regimens on haematological and biochemical parameters in the rat models were studied. Immunohistochemistry, immunofluorescence and immunoblot techniques were used to study the expression pattern of the related proteins in the human CRC cells pre- and post-treatment. Double contrast barium enema, post-mortem examination and histological analyses were used to confirm tumour growth and the effect of the treatment in vivo in rat models. Notably, we found in human mucinous CRC, a significant increase in expression of the BIRC7/Livin post-FOLFOX treatment compared with pre-treatment (p = 0.0001). This increase provides new insights into the prognostic role of BIRC7/Livin in evasion of apoptosis and facilitation of treatment resistance, local recurrence and metastasis particularly among mucinous CRCs post-FOLFOX chemotherapy. These poor prognostic features in the CRC may be further compounded by the significant suppression of DARC, PD-L1, PMS2 and overexpression of MSH2 and anti-apoptotic Bcl-2 and p53 proteins observed in our study (p < 0.05). Importantly, we found a significant reduction in expression of BIRC7/Livin and reactivation of DARC and PD-L1 with a surge in Annexin V expression in rat models of CRC cells post-treatment with a sequential dose of aspirin plus FOLFOX compared with other treatments in vivo (p <0.05). The mechanistic rational of these effects underscores the importance of expanded concept of possible aspirin combination therapy with FOLFOX sequentially in future CRC management. Validation of our findings through randomized clinical trials of aspirin plus FOLFOX sequentially in patients with CRC is therefore warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Aspirin/pharmacology , Biomarkers, Tumor/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Annexin A5/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , B7-H1 Antigen/metabolism , Cell Line, Tumor , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/pathology , DNA Mismatch Repair/drug effects , Drug Interactions , Duffy Blood-Group System/metabolism , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Humans , Inhibitor of Apoptosis Proteins/metabolism , Leucovorin/pharmacology , Leucovorin/therapeutic use , Male , Mismatch Repair Endonuclease PMS2/metabolism , MutS Homolog 2 Protein/metabolism , Neoplasm Proteins/metabolism , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Prognosis , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Receptors, Cell Surface/metabolism , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Cisplatin (CDDP) is one of the most effective chemotherapeutic agents, used for the treatment of diverse tumors, including neuroblastoma and glioblastoma. CDDP induces cell death through different apoptotic pathways. Despite its clinical benefits, CDDP causes several side effects and drug resistance.[Pt(O,O'-acac)(γ-acac)(DMS)], namely PtAcacDMS, a new platinum(II) complex containing two acetylacetonate (acac) and a dimethylsulphide (DMS) in the coordination sphere of metal, has been recently synthesized and showed 100 times higher cytotoxicity than CDDP. Additionally, PtAcacDMS was associated to a decreased neurotoxicity in developing rat central nervous system, also displaying great antitumor and antiangiogenic activity both in vivo and in vitro. Thus, based on the knowledge that several chemotherapeutics induce cancer cell death through an aberrant increase in [Ca2+]i, in the present in vitro study we compared CDDP and PtAcacDMS effects on apoptosis and intracellular Ca2+ dynamics in human glioblastoma T98G cells, applying a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, electron microscopy, Western blotting, qRT-PCR, and epifluorescent Ca2+ imaging. The results confirmed that (i) platinum compounds may induce cell death through an aberrant increase in [Ca2+]i and (ii) PtAcacDMS exerted stronger cytotoxic effect than CDDP, associated to a larger increase in resting [Ca2+]i. These findings corroborate the use of PtAcacDMS as a promising approach to improve Pt-based chemotherapy against gliomas, either by inducing a chemosensitization or reducing chemoresistance in cell lineages resilient to CDDP treatment.
Subject(s)
Brain Neoplasms/pathology , Cisplatin/adverse effects , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Glioma/pathology , Organoplatinum Compounds/pharmacology , Apoptosis/drug effects , Brain Neoplasms/genetics , Brain Neoplasms/ultrastructure , Calcium/metabolism , Cell Death/drug effects , Cell Line, Tumor , Cytoskeleton/drug effects , Cytoskeleton/metabolism , Drug Resistance, Neoplasm/drug effects , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Glioma/genetics , Glioma/ultrastructure , Homeostasis/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Nerve Tissue Proteins/metabolism , ORAI1 Protein/genetics , ORAI1 Protein/metabolism , Plasma Membrane Calcium-Transporting ATPases/metabolism , Poly(ADP-ribose) Polymerases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
PURPOSE: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer. EXPERIMENTAL DESIGN: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer. RESULTS: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer. CONCLUSIONS: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biological Assay/methods , Biomarkers, Tumor/genetics , Colorectal Neoplasms/therapy , DNA Damage/immunology , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant/methods , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , DNA Damage/drug effects , DNA Mutational Analysis , Female , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Gene Expression Profiling , Humans , Leucovorin/pharmacology , Leucovorin/therapeutic use , Male , Microsatellite Instability , Middle Aged , Mutation , Neoadjuvant Therapy/methods , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Progression-Free Survival , Randomized Controlled Trials as TopicABSTRACT
Combinational administration of photothermal therapy (PTT) and chemotherapy (CT) shows great potential in improving the efficiency of tumor treatment. Herein, we designed a novel nanocomposite Pt@Bi2Te3 composed of bismuth telluride (Bi2Te3) nanoparticles and platinum(IV) prodrugs (Pt) for PTT-CT combination therapy. The obtained Bi2Te3 was synthesized by a simple solvothermal method and modified by polyethylene glycol, which exhibited excellent photothermal (PT) efficiency and stability and could also serve as a bimodal bioimaging contrast agent in PT and photoacoustic (PA) imaging. In vitro experiment results showed that the nanocomposite Pt@Bi2Te3 could effectively increase the uptake of platinum in cancer cells, which could kill tumor cells through the combined effect of PTT and CT. Furthermore, combination therapy of cancer in vivo was achieved with obvious tumor-growth inhibition without inducing observed side effects. We revealed the great potential of Bi2Te3 nanocomposites in increasing therapeutic efficiency by PTT-CT therapy and PA-PT imaging.
Subject(s)
Antineoplastic Agents/chemistry , Bismuth/chemistry , Nanoparticles/chemistry , Organoplatinum Compounds/chemistry , Prodrugs/chemistry , Tellurium/chemistry , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Combined Modality Therapy/methods , Diagnostic Imaging/methods , Drug Delivery Systems/methods , Drug Liberation , Female , Humans , Mice , Mice, Inbred BALB C , Nanocomposites/chemistry , Organoplatinum Compounds/pharmacology , Photoacoustic Techniques/methods , Phototherapy/methods , Polyethylene Glycols/chemistry , Prodrugs/pharmacologyABSTRACT
BACKGROUND Depression is the 5th most prevalent disorder adversely affecting the health of humans worldwide. The present study evaluated the antidepressant effect of ginkgolide-platinum(II) complex in vivo in a mice model of CMS-induced depression. MATERIAL AND METHODS Depression was induced in mice by social isolation followed by chronic mild stress. After stress, the mice were assigned randomly to a model group, a 3 mg/kg group, a 6 mg/kg group, and a 12 mg/kg group. The mice in the 3 treatment groups were intraperitoneally injected with a single dose of 3.0, 6.0, or 12.0 mg/kg GPt(II) on day 11 of stress. The behavioral changes in mice were analyzed on day 21 of GPt(II) treatment by suspension and open field tests. RESULTS The GPt(II) treatment significantly increased the numbers of crossings and rearings in CMS mice. Treatment of mice with GPt(II) significantly elevated dopamine, BDNF, and serotonin levels in hippocampus tissues. The CMS-mediated reduction of neuropeptide production in the hippocampus tissues was significantly alleviated by GPt(II) treatment (P<0.05). The GPt(II) treatment suppressed the effect on CMS-induced elevated level of MAO-A in hippocampus tissues. Treatment with GPt(II) significantly repressed caspase-3 activation induced by CMS in the hippocampus tissues of mice. The GPt(II) treatment significantly (P<0.05) upregulated Hsp70 mRNA level in depression model mice. The levels of dopamine, serotonin, and BDNF were increased from 187.83±8.53, 289.65±10.76, and 7.98±1.87 ng/g, respectively, in the model group to 657.63±24.47, 720.54±28.09, and 22.56±3.11 ng/g, respectively, in the 12 mg/kg GPt(II) treatment group. CONCLUSIONS GPt(II) treatment significantly relieved characteristics of depression in the mice through upregulation of neurotransmitter, neuropeptide, and Hsp70 expression. Moreover, GPt(II) downregulated monoamine oxidase-A levels in the mouse hippocampus tissues. Therefore, further research is warranted on the possible therapeutic effect of GPt(II) in the treatment of depression.
Subject(s)
Depression/drug therapy , Depression/metabolism , Dopamine/metabolism , Ginkgolides/pharmacology , Organoplatinum Compounds/pharmacology , Serotonin/metabolism , Animals , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Berberine/analogs & derivatives , Berberine/metabolism , Berberine/pharmacology , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , HSP70 Heat-Shock Proteins/metabolism , Hippocampus/metabolism , Male , Mice , Mice, Inbred C57BL , Monoamine Oxidase/metabolism , Neuropeptide Y/metabolism , Neurotransmitter Agents/metabolism , Stress, Psychological/drug therapyABSTRACT
Platinum drugs, such as cisplatin (DDP) and carboplatin (CBP), are the main drugs for the treatment of lung cancer, but their practical clinical application is limited by severe toxicity and acquired drug resistance. Our previous study has indicated that diplatin, [2-(4-(diethyl-amino)butyl)malonate-O,O']-[(1R,2R)-cyclohexane-1,2-diamine N,N'] platinum (II) phosphate, a novel water-soluble platinum complex, could overcome DDP-resistant cells and was less toxic than comparable platinum drugs. In the present study, the effects and mechanisms of diplatin were further evaluated for its development as a novel anti-lung cancer platinum drug. Here, we found diplatin down-regulated the viability of H460 and LTEP-A-2 cells in a dose-dependent manner. Nude mice administrated with diplatin (30-120 mg/kg) via tail vein injection dose-dependently inhibited the growth of H460 and LTEP-A-2 xenograft tumors, whose action mainly correlated with the induction of tumor apoptosis. Particularly, the exposure of lung cancer cells or xenograft tumors to diplatin resulted in elevated Fas level, and knockdown of Fas ameliorated diplatin-induced cells apoptosis. Overall, we suggest that diplatin has potent anti-tumor activity, which probably acts through Fas-mediated signaling pathway.
Subject(s)
Antineoplastic Agents/therapeutic use , Fas Ligand Protein/metabolism , Lung Neoplasms/drug therapy , Organoplatinum Compounds/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line , Cell Survival/drug effects , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice, Inbred BALB C , Mice, Nude , Organoplatinum Compounds/pharmacology , Solubility , Water/chemistrySubject(s)
Colorectal Neoplasms/therapy , Immune Checkpoint Inhibitors/therapeutic use , Liver Neoplasms/therapy , Microsatellite Instability , Adult , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , BRCA1 Protein/genetics , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Camptothecin/therapeutic use , Chemotherapy, Adjuvant/methods , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , DNA Mismatch Repair , Disease Progression , Drug Resistance, Neoplasm/genetics , Female , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Hepatectomy , Humans , Immune Checkpoint Inhibitors/pharmacology , Leucovorin/pharmacology , Leucovorin/therapeutic use , Liver Neoplasms/genetics , Liver Neoplasms/secondary , Neoadjuvant Therapy/methods , Nivolumab/pharmacology , Nivolumab/therapeutic use , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Treatment OutcomeABSTRACT
In the present study, we utilize a poly[2-(N,N-dimethylamino)ethyl methacrylate]-poly(ε-caprolactone) (PDMA-PCL) micellar template-based gold nanoshell as a nanocarrier of a platinum-based chemotherapeutic drug, dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt). The gold nanoshells not only function as a drug delivery platform but also provide a remarkable photothermal effect, resulting in synergistically combined chemo-photothermal therapy. With the positively charged outstretched hydrophilic PDMA segments, chloroauric anions are attracted to the PDMA-PCL micellar surface and reduced to gold atoms in situ, forming small seeds that nucleate the subsequent growth of gold nanoshells. The DACHPt-loaded gold nanoshells possess strong absorption in the near-infrared (NIR) region and outstanding photothermal conversion effect; thus, they can promote a temperature increase that is sufficient to ablate tumor cells under NIR laser irradiation at a moderate power density (1 W/cm2). Furthermore, by exploiting the synergistic effects of platinum-based chemotherapy and photothermal therapy, the DACHPt-loaded gold nanoshells exhibited a profound inhibition of tumor growth compared to chemotherapy or photothermal therapy alone. Therefore, the platinum(II)-loaded gold nanoshells that we proposed herein may be a potential alternative for efficient curative therapy for colorectal cancer.
Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Gold , Hyperthermia, Induced , Metal Nanoparticles , Organoplatinum Compounds , Phototherapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Gold/chemistry , Gold/pharmacology , HCT116 Cells , HT29 Cells , Humans , Male , Metal Nanoparticles/chemistry , Metal Nanoparticles/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: To explore the efficacy and safety of thoracic hyperthermia perfusion with recombinant human endostatin plus nedaplatin in the treatment of pleural effusion in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion, and among them, 61 received thoracic hyperthermic perfusion with recombinant human endostatin (ES) plus nedaplatin (Endostatin group), while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone (Cisplatin group). The short-term efficacy, changes in the pleural effusion and serum immunological indicators before and after treatment, quality of life, and incidence of adverse reactions were compared between the two groups of patients. Finally, the progression of pleural effusion in patients were followed up and recorded. RESULTS: After treatment, the overall response rate of patients in Endostatin group was considerably higher than that in Cisplatin group (p=0.030). At 2 weeks after treatment, the level of alanine transferase (ALT) rose notably, while that of carcinoembryonic antigen (CEA) declined dramatically in both groups of patients, and the patients in Endostatin group had markedly lower levels of ALT and CEA than those in Cisplatin group (p=0.007, p=0.003). After treatment, the Karnofsky Performance status (KPS) score of patients was prominently raised in the two groups, and Endostatin group exhibited considerably higher KPS scores than Cisplatin group (p=0.045). The incidence rates of nausea and vomiting as well as diarrhea in Endostatin group were prominently lower than those in Cisplatin group (p=0.039, p=0.048). According to the follow-up results, the median time to the progression of pleural effusion in Endostatin group was markedly longer than that in Cisplatin group (p=0.008). CONCLUSIONS: Compared with the thoracic hyperthermic perfusion with cisplatin alone, the thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin showed dramatically potential efficacy, decrease of the incidence rate of adverse reactions in the digestive system, improvement of quality of life of patients, and prolongation of progression of pleural effusion.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Endostatins/therapeutic use , Lung Neoplasms/drug therapy , Organoplatinum Compounds/therapeutic use , Pleural Effusion, Malignant/drug therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/complications , Endostatins/pharmacology , Female , Humans , Hyperthermia, Induced , Lung Neoplasms/complications , Male , Middle Aged , Organoplatinum Compounds/pharmacology , Retrospective StudiesABSTRACT
Current chemotherapeutics for metastatic colorectal cancers have limited success and are extremely toxic due to nonselective targeting. Some natural extracts have been traditionally taken and have shown anticancer activity. These extracts have multiple phytochemicals that can target different pathways selectively in cancer cells. We have shown previously that lemongrass (Cymbopogon citratus) extract is effective at inducing cell death in human lymphomas. However, the efficacy of lemongrass extract on human colorectal cancer has not been investigated. Furthermore, its interactions with current chemotherapies for colon cancer is unknown. In this article, we report the anticancer effects of ethanolic lemongrass extract in colorectal cancer models, and importantly, its interactions with FOLFOX and Taxol. Lemongrass extract induced apoptosis in colon cancer cells in a time and dose-dependent manner without harming healthy cells in vitro. Oral administration of lemongrass extract was well tolerated and effective at inhibiting colon cancer xenograft growth in mice. It enhanced the anticancer efficacy of FOLFOX and, interestingly, inhibited FOLFOX-related weight loss in animals given the combination treatment. Furthermore, feeding lemongrass extract to APCmin/+ transgenic mice led to the reduction of intestinal tumors, indicating its preventative potential. Therefore, this natural extract has potential to be developed as a supplemental treatment for colorectal cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinogenesis/drug effects , Colonic Neoplasms/drug therapy , Cymbopogon/chemistry , Plant Extracts/pharmacology , Animals , Apoptosis/drug effects , Cell Line , Cell Transformation, Neoplastic/drug effects , Ethanol/chemistry , Fluorouracil/pharmacology , HCT116 Cells , HT29 Cells , Humans , Leucovorin/pharmacology , Mice , Mice, Nude , Mice, Transgenic , Organoplatinum Compounds/pharmacology , Xenograft Model Antitumor Assays/methodsABSTRACT
Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Bile Duct Neoplasms/therapy , Cholangiocarcinoma/therapy , Liver Neoplasms/therapy , Lymphatic Metastasis/therapy , Nivolumab/therapeutic use , Aged , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/immunology , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Bile Ducts, Intrahepatic/surgery , Capecitabine/pharmacology , Capecitabine/therapeutic use , Chemoradiotherapy, Adjuvant/methods , Cholangiocarcinoma/genetics , Cholangiocarcinoma/immunology , Cholangiocarcinoma/secondary , DNA Mutational Analysis , Drug Resistance, Neoplasm/genetics , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Humans , Inguinal Canal/pathology , Leucovorin/pharmacology , Leucovorin/therapeutic use , Liver/diagnostic imaging , Liver/pathology , Liver Neoplasms/secondary , Lymphatic Metastasis/diagnostic imaging , Male , Microsatellite Instability , Neoplasm, Residual , Nivolumab/pharmacology , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Positron Emission Tomography Computed Tomography , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Treatment OutcomeABSTRACT
Oxaliplatin-based chemotherapy (FOLFOX [folinic acid, fluorouracil, oxaliplatin] or XELOX [oxaliplatin, capecitabine; also called CAPOX]) for 6 months is the current standard for adjuvant therapy of stage III colon cancer patients with good performance status. However, these regimens are associated with significant toxicities, including myelosuppression, diarrhea, and oxaliplatin-induced, cumulative, dose-dependent neurotoxicity. A reduced duration of adjuvant therapy, which would reduce overall toxicity while maintaining overall clinical efficacy, would be optimal. The goal of the International Duration Evaluation of Adjuvant (IDEA) study was to evaluate the noninferiority of 3-month compared with 6-month adjuvant oxaliplatin-based treatment in stage III colon cancer using a prospectively designed pooled analysis of 6 concurrently conducted phase III randomized trials. Herein, we review the findings of the IDEA study and discuss the optimal duration of oxaliplatin-based adjuvant chemotherapy using patient-based risk factors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Colonic Neoplasms , Deoxycytidine/analogs & derivatives , Drug-Related Side Effects and Adverse Reactions/prevention & control , Fluorouracil/analogs & derivatives , Medication Therapy Management , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine , Chemotherapy, Adjuvant , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Humans , Leucovorin/pharmacology , Neoplasm Staging , Organoplatinum Compounds/pharmacology , Oxaloacetates , Time Factors , Treatment OutcomeABSTRACT
Cancer cells typically shift their metabolism to aerobic glycolysis to fulfill the demand of energy and macromolecules to support their proliferation. Glucose transporter (GLUT) family-mediated glucose transport is the pacesetter of aerobic glycolysis and, thus, is critical for tumor cell metabolism. Yin Yang 1 (YY1) is an oncogene crucial for tumorigenesis; however, its role in tumor cell glucose metabolism remains unclear. Here, we revealed that YY1 activates GLUT3 transcription by directly binding to its promoter and, concomitantly, enhances tumor cell aerobic glycolysis. This regulatory effect of YY1 on glucose entry into the cells is critical for YY1-induced tumor cell proliferation and tumorigenesis. Intriguingly, YY1 regulation of GLUT3 expression, and, subsequently, of tumor cell aerobic glycolysis and tumorigenesis, occurs p53-independently. Our results also showed that clinical drug oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis. Together, these results link YY1's tumorigenic potential with the critical first step of aerobic glycolysis. Thus, our novel findings not only provide new insights into the complex role of YY1 in tumorigenesis but also indicate the potential of YY1 as a target for cancer therapy irrespective of the p53 status.
Subject(s)
Carcinogenesis/genetics , Glucose Transporter Type 3/genetics , Walker-Warburg Syndrome/genetics , YY1 Transcription Factor/genetics , Animals , Carcinogenesis/drug effects , Carcinogenesis/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Glycolysis/drug effects , Glycolysis/genetics , HCT116 Cells , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Organoplatinum Compounds/pharmacology , Oxaliplatin , Promoter Regions, Genetic/genetics , Tumor Suppressor Protein p53/genetics , Walker-Warburg Syndrome/pathologyABSTRACT
The platinum-based drugs cisplatin, carboplatin and oxaliplatin are regularly prescribed in the treatment of cancer and while they are effective, their use is limited by their severe, dose-limiting side effects (also referred to as adverse effects/events). In total, a cancer patient can experience any combination of around 40 specific side effects. The dose-limiting side effect for cisplatin is nephrotoxicity, for carboplatin it is myelosuppression, and for oxaliplatin it is neurotoxicity. Other common side effects include anaphylaxis, cytopenias (including leukopenia and neutropenia, thrombocytopenia, and anaemia), hepatotoxicity, ototoxicity, cardiotoxicity, nausea and vomiting, diarrhea, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, and asthenia. The side effects may require patients to be prescribed dose reductions in their platinum drugs of between 25 and 100%. Furthermore, patients require extensive monitoring of their biochemistries, kidney and liver function, and depending on the drug, hearing tests. Finally, patients are commonly co-prescribed additional non-chemotherapy based drugs to treat the side effects which can include antiemetics, antibiotics and myeloid growth factors, mannitol, propafenone, saline hyperhydration, magnesium supplements, monoclonal antibody cytokine blockers, and antioxidants.
Subject(s)
Antineoplastic Agents/adverse effects , Neoplasms/drug therapy , Organoplatinum Compounds/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Structure , Neoplasms/pathology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
BACKGROUND: There is limited evidence assessing the effects of omega-3 polyunsaturated fatty acids (PUFAs) on oesophageal adenocarcinoma, both in vitro and in vivo. We evaluated the effects of the omega-3 PUFA and oxaliplatin on OE33 and OE19 cells. METHOD: The two oesophageal cells were treated with Omegaven® (fish oil emulsion), EPA, DHA and oxaliplatin and incubated for up to 144 h. RESULTS: The following inhibitory effects were observed on OE33 cells: EPA reduced cell growth by 39% (p = 0.001), DHA by 59% (p < 0.000) and Oxaliplatin by 77% (p < 0.000). For OE19 cells, the EPA reduced growth by 1% (p = 0.992), DHA by 26% (p = 0.019) and oxaliplatin by 76% (p < 0.000). For both cells, Omegaven® resulted in reduced cell growth at intermediate concentrations (20-40 µM) and increased cell growth at low (10 µM) and high (50 µM) concentrations. DHA, Omegaven® and oxaliplatin were associated with significant downregulation of VEGF and p53 protein, and upregulation of p21 protein. DHA, Omegaven® and Oxaliplatin also led to significant downregulation of the total ERK1/2 and Akt proteins. CONCLUSION: DHA, Omegaven® and oxaliplatin were associated with downregulation of p53 and VEGF in both cells. Of the PUFAs studied, DHA alone or in combination (Omegaven®) had greater in vitro anti-cancer effects than EPA alone.
Subject(s)
Adenocarcinoma/drug therapy , Esophageal Neoplasms/drug therapy , Fatty Acids, Omega-3/pharmacology , Fish Oils/pharmacology , Organoplatinum Compounds/pharmacology , Signal Transduction/drug effects , Adenocarcinoma/metabolism , Adenocarcinoma/physiopathology , Aged , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Cytokines/drug effects , Docosahexaenoic Acids/pharmacology , Docosahexaenoic Acids/therapeutic use , Down-Regulation , Eicosapentaenoic Acid/pharmacology , Eicosapentaenoic Acid/therapeutic use , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/physiopathology , Fatty Acids, Omega-3/therapeutic use , Female , Fish Oils/therapeutic use , Gene Expression Regulation, Neoplastic , Humans , Male , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Triglycerides , Tumor Suppressor Protein p53/drug effects , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Vascular Endothelial Growth Factors/drug effects , Vascular Endothelial Growth Factors/genetics , Vascular Endothelial Growth Factors/metabolismABSTRACT
Chemotherapy induced neuropathy causes excruciating pain to cancer patients. Wen-Luo-Tong (WLT), a traditional Chinese medicinal compound, has been used to alleviate anti-cancer drug such as oxaliplatin-induced neuropathic pain for many years. However, the current route of administration of WLT is inconvenient and the active ingredients and mechanism of action of WLT are still unclear. To address these issues, we developed a novel formulation of WLT (W/O microemulsion) for the ease of application. New ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) methods were employed for analysis of the ingredients. We identified seven ingredients that penetrated through the skin into the Franz cell receptor solution and four of those ingredients were retained in skin tissue when WLT microemulsion was applied. We tested the microemulsion formulation on an oxaliplatin-induced neuropathy rat model and showed that this formulation significantly decreased oxaliplatin-induced mechanical hyperalgesia responses. Schwann cells (SCs) viability experiment in vitro was studied to test the protective effect of the identified seven ingredients. The result showed that Hydroxysafflor Yellow A, icariin, epimedin B and 4-dihydroxybenzoic acid significantly increased the viability of SCs after injured by Oxaliplatin. Our report presents the first novel formulation of WLT with neuroprotective effect and ease of use, which has potential for clinical applications.