-
Oxidative Medicine and Cellular... 2019Redox homeostasis is essential for the maintenance of diverse cellular processes. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells as a... (Review)
Review
Redox homeostasis is essential for the maintenance of diverse cellular processes. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells as a result of hypermetabolism, but the redox balance is maintained in cancer cells due to their marked antioxidant capacity. Recently, anticancer therapies that induce oxidative stress by increasing ROS and/or inhibiting antioxidant processes have received significant attention. The acceleration of accumulative ROS disrupts redox homeostasis and causes severe damage in cancer cells. In this review, we describe ROS-inducing cancer therapy and the anticancer mechanism employed by prooxidative agents. To understand the comprehensive biological response to certain prooxidative anticancer drugs such as 2-methoxyestradiol, buthionine sulfoximine, cisplatin, doxorubicin, imexon, and motexafin gadolinium, we propose and visualize the drug-gene, drug-cell process, and drug-disease interactions involved in oxidative stress induction and antioxidant process inhibition as well as specific side effects of these drugs using pathway analysis with a big data-based text-mining approach. Our review will be helpful to improve the therapeutic effects of anticancer drugs by providing information about biological changes that occur in response to prooxidants. For future directions, there is still a need for pharmacogenomic studies on prooxidative agents as well as the molecular mechanisms underlying the effects of the prooxidants and/or antioxidant-inhibitor agents for effective anticancer therapy through selective killing of cancer cells.
Topics: 2-Methoxyestradiol; Animals; Antineoplastic Agents; Homeostasis; Humans; Neoplasms; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 31929855
DOI: 10.1155/2019/5381692 -
Nature Communications Oct 2023Gadolinium (Gd)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient...
Gadolinium (Gd)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient radiosensitization efficacy. Little attention has been given to using nanovesicles to improve its efficacy. Herein, Gd-Tex is transformed into building blocks "Gd-Tex-lipids" to self-assemble nanovesicles called Gd-nanotexaphyrins (Gd-NTs), realizing high density packing of Gd-Tex in a single nanovesicle and achieving high Gd-Tex accumulation in tumors. To elucidate the impact of O concentration on Gd-Tex radiosensitization, myoglobin (Mb) is loaded into Gd-NTs (Mb@Gd-NTs), resulting in efficient relief of tumor hypoxia and significant enhancement of Gd-Tex radiosensitization, eventually inducing the obvious long-term antitumor immune memory to inhibit tumor recurrence. In addition to Gd, the versatile Mb@Gd-NTs can also chelate Lu (Mb@Lu/Gd-NTs), enabling SPECT/MRI dual-modality imaging for accurately monitoring drug delivery in real-time. This "one-for-all" nanoplatform with the capability of chelating various trivalent metal ions exhibits broad clinical application prospects in imaging-guided radiosensitization therapy.
Topics: Humans; Gadolinium; Myoglobin; Oxygen; Radiation-Sensitizing Agents; Neoplasms; Magnetic Resonance Imaging
PubMed: 37794000
DOI: 10.1038/s41467-023-41782-w -
Radiology May 2016To investigate the possibility of using motexafin gadolinium (MGd)-enhanced molecular magnetic resonance (MR) imaging and optical imaging to identify the true margins of...
PURPOSE
To investigate the possibility of using motexafin gadolinium (MGd)-enhanced molecular magnetic resonance (MR) imaging and optical imaging to identify the true margins of gliomas.
MATERIALS AND METHODS
The animal protocol was approved by the institutional animal care and use committee. Thirty-six Sprague-Dawley rats with gliomas were randomized into six groups of six rats. Five groups were euthanized 15, 30, 60, 120, and 240 minutes after intravenous administration of 6 mg/kg of MGd, while one group received only saline solution as a control group. After craniotomy, optical imaging and T1-weighted MR imaging were performed to identify the tumor margins. One-way analysis of variance was used to compare optical photon intensity and MR imaging signal-to-noise ratios. Histologic analysis was performed to confirm the intracellular uptake of MGd by tumor cells and to correlate the tumor margins delineated on both optical and MR images.
RESULTS
Both optical imaging and T1-weighted MR imaging showed tumor margins. The highest optical photon intensity (2.6 × 10(8) photons per second per mm(2) ± 2.3 × 10(7); analysis of variance, P < .001) and MR signal-to-noise ratio (77.61 ± 2.52; analysis of variance, P = .006) were reached at 15-30 minutes after administration of MGd, with continued tumor visibility at 2-4 hours. Examination with confocal microscopy allowed confirmation that the fluorescence of optical images and MR imaging T1 enhancement exclusively originated from MGd that accumulated in the cytoplasm of tumor cells.
CONCLUSION
MGd-enhanced optical and MR imaging can allow determination of glioma tumor margins at the optimal time of 15-120 minutes after administration of MGd. Clinical application of these results may allow complete removal of gliomas in a hybrid surgical setting in which intraoperative optical and MR imaging are available.
Topics: Animals; Brain Neoplasms; Contrast Media; Craniotomy; Disease Models, Animal; Glioma; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Metalloporphyrins; Microscopy, Confocal; Molecular Imaging; Random Allocation; Rats; Rats, Sprague-Dawley; Signal-To-Noise Ratio; Tumor Cells, Cultured
PubMed: 26599802
DOI: 10.1148/radiol.2015150895 -
International Journal of Radiation... Apr 2015The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy...
Phase 1/2 trials of Temozolomide, Motexafin Gadolinium, and 60-Gy fractionated radiation for newly diagnosed supratentorial glioblastoma multiforme: final results of RTOG 0513.
PURPOSE
The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls.
METHODS AND MATERIALS
Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method.
RESULTS
In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy.
CONCLUSIONS
Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Dacarbazine; Disease-Free Survival; Dose Fractionation, Radiation; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Metalloporphyrins; Multivariate Analysis; Supratentorial Neoplasms; Temozolomide
PubMed: 25832688
DOI: 10.1016/j.ijrobp.2014.12.050 -
Annals of Translational Medicine Mar 2020Studies have increasingly shown that carbamoyl phosphate synthetase 1 () plays a vital role in the occurrence and development of human malignant disease. Unfortunately,...
BACKGROUND
Studies have increasingly shown that carbamoyl phosphate synthetase 1 () plays a vital role in the occurrence and development of human malignant disease. Unfortunately, the detailed function of in the development and prognosis of lung cancer, especially lung adenocarcinoma (LADC), is still not fully understood. In this research, we performed a comprehensive bioinformatics analysis with respect to the function of in human LADC.
METHODS
Several biological databases including UALCAN, GEPIA and Oncomine were used to analyze the expression of in LADC. Meanwhile, TCGA and GEO databases were utilized to analyze relevant clinical data. In addition, databases including Methsurv, etc., were used to analyze methylation levels in LADC.
RESULTS
The Oncomine platform, UALCAN and gene expression profiling interactive analysis (GEPIA) were used and revealed that the expression levels of were significantly increased in LADC tissues. Furthermore, we analyzed the methylation level of in LADC and found that cases with high levels of showed hypomethylated . The clinical data from the Wanderer database, which is linked to The Cancer Genome Atlas (TCGA) database, demonstrated that the expression and methylation values of were both significantly related to the clinical characteristics and prognosis of LADC. Through analysis of the dataset from the Gene Expression Omnibus (GEO) database, we found that the expression level of was markedly downregulated in human A549 lung cancer cells treated with the chemotherapeutic drug motexafin gadolinium (MGd) in a time-dependent manner.
CONCLUSIONS
Our work indicated that is upregulated in LADC samples and that might be used as a potential biomarker for the diagnostic and prognostic evaluation of LADC. Determining the detailed biological function of in LADC tissues will provide promising and insightful information for our further study.
PubMed: 32355785
DOI: 10.21037/atm.2020.02.146 -
Cancers Sep 2022Background: Residual viable tumor cells after ablation at the tumor periphery serve as the source for tumor recurrence, leading to treatment failure. Purpose: To develop...
Background: Residual viable tumor cells after ablation at the tumor periphery serve as the source for tumor recurrence, leading to treatment failure. Purpose: To develop a novel three-dimensional (3D) multi-modal perfusion-thermal electrode system completely eradicating medium-to-large malignancies. Materials and Methods: This study included five steps: (i) design of the new system; (ii) production of the new system; (iii) ex vivo evaluation of its perfusion-thermal functions; (iv) mathematic modeling and computer simulation to confirm the optimal temperature profiles during the thermal ablation process, and; (v) in vivo technical validation using five living rabbits with orthotopic liver tumors. Results: In ex vivo experiments, gross pathology and optical imaging demonstrated the successful spherical distribution/deposition of motexafin gadolinium administered through the new electrode, with a temperature gradient from the electrode core at 80 °C to its periphery at 42 °C. An excellent repeatable correlation of temperature profiles at varying spots, from the center to periphery of the liver tumor, was found between the mathematic simulation and actual animal tumor models (Pearson coefficient ≥0.977). For in vivo validation, indocyanine green (ICG) was directly delivered into the peritumoral zones during simultaneous generation of central tumoral lethal radiofrequency (RF) heat (>60 °C) and peritumoral sublethal RF hyperthermia (<60 °C). Both optical imaging and fluorescent microscopy confirmed successful peritumoral ICG distribution/deposition with increased heat shock protein 70 expression. Conclusion: This new 3D, perfusion-thermal electrode system provided the evidence on the potential to enable simultaneous delivery of therapeutic agents and RF hyperthermia into the difficult-to-treat peritumoral zones, creating a new strategy to address the critical limitation, i.e., the high incidence of residual and recurrent tumor following thermal ablation of unresectable medium-to-large and irregular tumors.
PubMed: 36230690
DOI: 10.3390/cancers14194768 -
Angewandte Chemie (International Ed. in... Oct 2016Water-soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to...
Water-soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co-incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt(IV) to Pt(II) promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt(IV) species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present "activation by reduction" approach may allow for the cancer-selective enhancement in the cytotoxicity of Pt(IV) prodrugs.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Electrochemical Techniques; Humans; Metalloporphyrins; Oxidation-Reduction; Platinum; Prodrugs
PubMed: 27377046
DOI: 10.1002/anie.201604236 -
Proceedings of the National Academy of... Mar 2020Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2)...
Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.
Topics: A549 Cells; Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; HCT116 Cells; Humans; Metalloporphyrins; Mice, Nude; Oxaliplatin; Prodrugs; Tissue Distribution; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 32179677
DOI: 10.1073/pnas.1914911117 -
Discover Oncology Apr 2024Radiation therapy (RT) plays an important role in the treatment of glioblastoma multiforme (GBM). However, inherent intrinsic resistance of tumors to radiation, coupled...
PURPOSE
Radiation therapy (RT) plays an important role in the treatment of glioblastoma multiforme (GBM). However, inherent intrinsic resistance of tumors to radiation, coupled with the need to consider the tolerance of normal tissues and the potential effects on neurocognitive function, impose constraints on the amount of RT that can be safely delivered. A strategy for augmenting the effectiveness of RT involves the utilization of radiation sensitizers (RS). Directly implanting RS-loaded fibrin glue (FG) into the tumor resection cavity would by-pass the blood brain barrier, potentially enhancing the impact of RT on tumor recurrence. This study investigated the ability of FG to incorporate and release, in non-degraded form, the radiation sensitizers 5-Fluorouracil (5FU) and Motexafin gadolinium (MGd).
METHODS
FG layers were created in a 24-well plate by combining thrombin, fibrinogen, and 5FU or MGd. Supernatants from these layers were collected at various intervals and added to F98 glioma spheroid cultures in 96-well plates. Radiation was applied either before or after RS application as single or fractionated dosages. Spheroid growth was monitored for 14 days.
RESULTS
Combined treatment of FG-released 5FU and RT significantly inhibited spheroid growth compared to RS or RT as a single treatment. As a free drug, MGd demonstrated its efficacy in reducing spheroid volume, but had diminished potency as a released RS. Fractionated radiation was more effective than single dose radiation.
CONCLUSION
Non-degraded RS was released from the FG for up to 72 h. FG-released 5FU greatly increased the efficacy of radiation therapy.
PubMed: 38573401
DOI: 10.1007/s12672-024-00953-x -
PloS One 2020COVID-19 is a critical pandemic that has affected human communities worldwide, and there is an urgent need to develop effective drugs. Although there are a large number...
BACKGROUND
COVID-19 is a critical pandemic that has affected human communities worldwide, and there is an urgent need to develop effective drugs. Although there are a large number of candidate drug compounds that may be useful for treating COVID-19, the evaluation of these drugs is time-consuming and costly. Thus, screening to identify potentially effective drugs prior to experimental validation is necessary.
METHOD
In this study, we applied the recently proposed method tensor decomposition (TD)-based unsupervised feature extraction (FE) to gene expression profiles of multiple lung cancer cell lines infected with severe acute respiratory syndrome coronavirus 2. We identified drug candidate compounds that significantly altered the expression of the 163 genes selected by TD-based unsupervised FE.
RESULTS
Numerous drugs were successfully screened, including many known antiviral drug compounds such as C646, chelerythrine chloride, canertinib, BX-795, sorafenib, sorafenib, QL-X-138, radicicol, A-443654, CGP-60474, alvocidib, mitoxantrone, QL-XII-47, geldanamycin, fluticasone, atorvastatin, quercetin, motexafin gadolinium, trovafloxacin, doxycycline, meloxicam, gentamicin, and dibromochloromethane. The screen also identified ivermectin, which was first identified as an anti-parasite drug and recently the drug was included in clinical trials for SARS-CoV-2.
CONCLUSIONS
The drugs screened using our strategy may be effective candidates for treating patients with COVID-19.
Topics: A549 Cells; Antiviral Agents; Betacoronavirus; Drug Discovery; Humans; SARS-CoV-2; Unsupervised Machine Learning
PubMed: 32915876
DOI: 10.1371/journal.pone.0238907