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Biochemistry. Biokhimiia May 2022Despite a high efficacy of chemotherapy in cancer treatment, acquired resistance of tumors to certain chemotherapeutic agents and frequent side effects remain the major...
Despite a high efficacy of chemotherapy in cancer treatment, acquired resistance of tumors to certain chemotherapeutic agents and frequent side effects remain the major factors of unfavorable prognosis in most cancer patients with unresectable, metastatic and recurrent forms of the disease. The discovery of novel molecular targets in tumors and development of new therapeutic approaches to enhance the efficiency of chemotherapeutic agents remain the biggest challenges in current oncology. Here we examined the ability of pyrrole-based heterocyclic compound 2-APC to sensitize tumor cells to the topoisomerase II inhibitor doxorubicin. The study was performed on human cancer cell lines treated with 2-APC, paclitaxel, and doxorubicin. Expression of DNA repair was investigated by Western blotting, whereas protein-protein interactions were examined by co-immunoprecipitation. The synergism between the chemotherapeutic agents was assessed with the Synergy Finder program. Doxorubicin exhibited moderate cytotoxic effect against cancer cell lines (in particular, osteosarcoma cell lines). 2-APC in non-toxic concentrations substantially potentiated the cytotoxic effect of doxorubicin and induced apoptosis of cancer cells. This activity of 2-APC was due to its ability to impair DNA damage repair by decreasing the content of Rad51 recombinase via promoting its proteasomal degradation. Similar effects were observed for paclitaxel, which affects tubulin polymerization. Therefore, chemotherapeutic agents and chemical compounds interfering with the microtubule dynamics can potentiate the cytotoxic effects of DNA-damaging chemotherapeutic agents via impairment of DNA damage repair mechanisms in cancer cells.
Topics: Antineoplastic Agents; DNA Damage; DNA Repair; Doxorubicin; Humans; Neoplasms; Paclitaxel; Pyrroles
PubMed: 35790377
DOI: 10.1134/S0006297922050017 -
Advanced Science (Weinheim,... Sep 2022Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be...
Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH-activated supramolecular nanoprodrug (PDNP) with a stepwise size shrinkage property is developed as a pyroptosis inducer to boost antitumor immune response. PDNPs comprise multiple poly(ethylene glycol) (PEG) and doxorubicin (DOX) drug-polymer hybrid repeating blocks conjugated by ultra-pH-sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its "stealth" property and ensure sufficient tumor accumulation. A sharp switch in particle size and detachment of PEG shielding can be triggered by the acidic extracellular pH to achieve deep intratumor penetration. Following endocytosis, second-stage size switching can be initiated by more acidic endolysosomes, and PDNPs disassociate into ultrasmall cargo to ensure accurate intracellular delivery. The cascaded pH activation of PDNPs can effectively elicit gasdermin E (GSDME)-mediated pyroptosis to enhance the immunological response. In combination with anti-PD-1 antibody, PDNPs can amplify tumor suppression and extend the survival of mice, which suggests a powerful immune adjuvant and pave the way for high-efficiency immune checkpoint blockade therapy.
Topics: Animals; Doxorubicin; Mice; Neoplasms; Polyethylene Glycols; Prodrugs; Pyroptosis
PubMed: 35869614
DOI: 10.1002/advs.202203353 -
Biopolymers Mar 2017We have investigated the interaction of the DNA molecule with the anticancer drug doxorubicin (doxo) by using three different experimental techniques: single molecule...
We have investigated the interaction of the DNA molecule with the anticancer drug doxorubicin (doxo) by using three different experimental techniques: single molecule stretching, single molecule imaging, and dynamic light scattering. Such techniques allowed us to get new insights on the mechanical behavior of the DNA-doxo complexes as well as on the physical chemistry of the interaction. First, the contour length data obtained from single molecule stretching were used to extract the physicochemical parameters of the DNA-doxo interaction under different buffer conditions. This analysis has proven that the physical chemistry of such interaction can be modulated by changing the ionic strength of the surrounding buffer. In particular we have found that at low ionc strengths doxo interacts with DNA by simple intercalation (no aggregation) and/or by forming bound dimers. For high ionic strengths, otherwise, doxo-doxo self-association is enhanced, giving rise to the formation of bound doxo aggregates composed by 3 to 4 molecules along the double-helix. On the other hand, the results obtained for the persistence length of the DNA-doxo complexes is strongly force-dependent, presenting different behaviors when measured with stretching or non-stretching techniques.
Topics: DNA; DNA Adducts; Doxorubicin; Dynamic Light Scattering; Microscopy, Atomic Force; Optical Tweezers
PubMed: 27718222
DOI: 10.1002/bip.22998 -
Acta Biomaterialia Mar 2023Image-guided stimulus-responsive theranostics are beneficial for identifying malignant lesions and integrating multiple cell-killing mechanisms to enhance tumor cell...
Image-guided stimulus-responsive theranostics are beneficial for identifying malignant lesions and integrating multiple cell-killing mechanisms to enhance tumor cell clearance. Herein, an intelligent dual-responsive nanostructure (HSPMH-DOX) was developed for magnetic resonance imaging (MRI)-guided synergistic chemo-photothermal therapy (PTT) and chemodynamic therapy (CDT). The core-shell nanostructure was synthesized by layering polydopamine (PDA), manganese oxide (MnO), and hyaluronic acid (HA) onto drug-loaded hollow mesoporous silica nanoparticles (HS). The constructed nanoagent has both endogenous and external dual responses. The tumor microenvironment (pH/GSH) can trigger the degradation of gatekeeper (MnO and PDA), resulting in the release of anti-tumor drugs, whereas external near-infrared light irradiation can accelerate the degradation process and generate local overheating, resulting in PTT. Notably, MnO can not only consume intracellular GSH to enhance CDT but also release Mn for precise localization of tumor tissues using MRI. Both in vitro and in vivo experiments showed that the prepared dual-response nanoagent satisfied biocompatibility, targeting, and the great efficiency of MRI-guided combined therapy. In animal models, combining chemo-PTT and CDT can eradicate tumors in less than two weeks. This work could pave the way for a wide range of stimulus-responsive synergistic theranostic applications, including MRI, chemo-photothermal therapy, and chemodynmic therapy. STATEMENT OF SIGNIFICANCE: Low bioavailability and severe side effects remain the major limitations of conventional cancer chemotherapy. Image-guided combination therapy can alleviate these problems and improve tumor-specific therapy. In the present study, the anticancer drug doxorubicin was encapsulated in a core-shell hollow mesoporous silica nanostructure (HSPMH-DOX), enabling MRI-guided targeted release under both endogenous and external dual stimuli. Moreover, the photothermal and nanoenzymatic effects of nanomedicine can cause local overheating in the tumor and amplify the intracellular CDT effect, accelerating tumor eradication. Systematic evaluations in vitro and in vivo confirmed that nanomedicine enables highly effective MRI-guided synergistic chemo-photothermal and chemodynamic therapy. This work offers a promising therapeutic strategy for precise anti-tumor applications.
Topics: Animals; Manganese Compounds; Photothermal Therapy; Phototherapy; Hyperthermia, Induced; Oxides; Antineoplastic Agents; Neoplasms; Nanostructures; Doxorubicin; Nanoparticles; Magnetic Resonance Imaging; Silicon Dioxide; Tumor Microenvironment
PubMed: 36586501
DOI: 10.1016/j.actbio.2022.12.053 -
International Immunopharmacology Jan 2023In clinical practice, major efforts are underway to identify appropriate drug combinations to boost anticancer activity while suppressing unwanted adverse effects. In...
In clinical practice, major efforts are underway to identify appropriate drug combinations to boost anticancer activity while suppressing unwanted adverse effects. In this regard, we evaluated the efficacy of combination treatment with the widely used chemotherapeutic drug doxorubicin along with the TGFβRI inhibitor galunisertib (LY2157299) in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The antiproliferative effects of these drugs as single agents or in combination against several B-NHL cell lines and the synergism of the drug combination were evaluated by calculating the combination index. To understand the putative molecular mechanism of drug synergism, the TGF-β and stress signaling pathways were analyzed after combination treatment. An aggressive lymphoma model was used to evaluate the anticancer activity and post-therapeutic immune response of the drug combination in vivo. Galunisertib sensitized various B-NHL cells to doxorubicin and in combination synergistically increased apoptosis. The antitumor activity of the drug combinations involved upregulation of p-P38 MAPK and inhibition of the TGF-β/Smad2/3 and PI3K/AKT signaling pathways. Combined drug treatment significantly reduced tumor growth and enhanced survival, indicating that the synergism between galunisertib and Dox observed in vitro was most likely retained in vivo. Based on the tumor-draining lymph node analysis, combination therapy results in better prognosis, including disappearance of disease-exacerbating regulatory T cells and prevention of CD8 T-cell exhaustion by downregulating MDSCs. Galunisertib synergistically potentiates the doxorubicin-mediated antitumor effect without aggravating the toxic effects and the ability to kickstart the immune system, supporting the clinical relevance of targeting TGF-βRI in combination with doxorubicin against lymphoma.
Topics: Humans; Phosphatidylinositol 3-Kinases; Doxorubicin; Neoplasms; Lymphoma; Transforming Growth Factor beta; Immune System; Drug Synergism; Cell Line, Tumor; Apoptosis
PubMed: 36470118
DOI: 10.1016/j.intimp.2022.109521 -
Environmental Research Sep 2023The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor... (Review)
Review
The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor elimination. Because of the biological and malignant features of cancer cells, they have ability of developing resistance to conventional therapies such as chemo- and radio-therapy. Pancreatic cancer (PC) is a malignant disease of gastrointestinal tract in which chemotherapy and radiotherapy are main tools in its treatment, and recently, nanocarriers have been emerged as promising structures in its therapy. The bioresponsive nanocarriers are able to respond to pH and redox, among others, in targeted delivery of cargo for specific treatment of PC. The loading drugs on the nanoparticles that can be synthetic or natural compounds, can help in more reduction in progression of PC through enhancing their intracellular accumulation in cancer cells. The encapsulation of genes in the nanoparticles can protect against degradation and promotes intracellular accumulation in tumor suppression. A new kind of therapy for cancer is phototherapy in which nanoparticles can stimulate both photothermal therapy and photodynamic therapy through hyperthermia and ROS overgeneration to trigger cell death in PC. Therefore, synergistic therapy of phototherapy with chemotherapy is performed in accelerating tumor suppression. One of the important functions of nanotechnology is selective targeting of PC cells in reducing side effects on normal cells. The nanostructures are capable of being surface functionalized with aptamers, proteins and antibodies to specifically target PC cells in suppressing their progression. Therefore, a specific therapy for PC is provided and future implications for diagnosis of PC is suggested.
Topics: Humans; Multifunctional Nanoparticles; Doxorubicin; Hyperthermia, Induced; Phototherapy; Neoplasms; Nanoparticles; Pancreatic Neoplasms; Cell Line, Tumor
PubMed: 37354932
DOI: 10.1016/j.envres.2023.116490 -
Biomaterials Oct 2018Multifunctional nanoparticles integrating cancer cell imaging and treatment modalities into a single platform are recognized as a promising approach; however, their...
Multifunctional nanoparticles integrating cancer cell imaging and treatment modalities into a single platform are recognized as a promising approach; however, their development currently remains a challenge. In this study, we synthesized magnetic field-inducible drug-eluting nanoparticles (MIDENs) by embedding superparamagnetic iron oxide nanoparticles (FeO; SPIONs) and cancer therapeutic drugs (doxorubicin; DOX) in a temperature-responsive poly (lactic-co-glycolic acid) (PLGA) nanomatrix. Application of an external alternating magnetic field (AMF) generated heat above 42 °C and subsequent transition of the PLGA polymer matrix (T = 42-45 °C) from the glassy to the rubbery state, facilitating the controlled release of the loaded DOX, ultimately allowing for simultaneous hyperthermia and local heat-triggered chemotherapy for efficient dual cancer treatment. The average size of the synthesized MIDENs was 172.1 ± 3.20 nm in diameter. In vitro studies showed that the MIDENs were cytocompatible and especially effective in destroying CT26 colon cancer cells with AMF application. In vivo studies revealed that the MIDENs enabled enhanced T contrast magnetic resonance imaging and a significant suppression of malignant tumor growth under an AMF. Our multifunctional MIDENs, composed of biocompatible substances and therapeutic/imaging modalities, will be greatly beneficial for cancer image-guided thermo-chemotherapy applications.
Topics: Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Delivery Systems; Humans; Hyperthermia, Induced; Magnetic Fields; Magnetite Nanoparticles
PubMed: 30055399
DOI: 10.1016/j.biomaterials.2018.07.028 -
Biomaterials Science May 2022Responsive nano-drug delivery systems, especially multi-responsive systems, based on the complex characteristics of the tumor microenvironment (TME), such as acidic pH,...
Responsive nano-drug delivery systems, especially multi-responsive systems, based on the complex characteristics of the tumor microenvironment (TME), such as acidic pH, hypoxia, and hydrogen peroxide (HO) overexpression, could enhance the biological activity of the drugs and reduce the side effects. In this study, a HO/glutathione (GSH) procedurally activatable nanoplatform (CuS-PEG/DOX NSs) was prepared as a vector of drugs released by responsive morphologic transformation and the co-activated Fenton agent for tumor-specific synergistic therapy. After endocytosis into tumor cells, CuS-PEG/DOX NSs were initially oxidized by over-expressed HO and transformed from nanosheets to nanoflowers, leading to the release of doxorubicin (DOX). Subsequently, CuS nanoflowers (CuS NFs) reacted with the local GSH, liberated a large number of copper ions, and induced GSH depletion. The released DOX promoted the generation of intracellular HO through cascade reactions, which were further utilized to facilitate the release of DOX and generate toxic hydroxyl radicals (˙OH) a copper-based Fenton-like reaction. CuS-PEG/DOX NSs sequentially activated by HO and GSH in tumor cells exhibited relatively high cytotoxicity, whereas normal cells were still alive. This nanoplatform, as a procedurally activatable delivery system, may have excellent potential for tumor-specific synergistic therapy.
Topics: Cell Line, Tumor; Copper; Doxorubicin; Glutathione; Hydrogen Peroxide; Tumor Microenvironment
PubMed: 35437541
DOI: 10.1039/d1bm01940f -
Biomaterials Feb 2022Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and...
Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation.
Topics: Cell Line, Tumor; Doxorubicin; Humans; Immunity; Nanoparticles; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Silicon Dioxide
PubMed: 35030436
DOI: 10.1016/j.biomaterials.2022.121368 -
Scientific Reports Mar 2024The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations,...
The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations, showing improved toxicity profiles. However, the adverse events associated with liposomal doxorubicin and CDOX have not yet been comprehensively evaluated in clinical settings. The FAERS data from January 2004 to December 2022 were collected to analyze the adverse events of liposomal doxorubicin and CDOX. Disproportionate analysis and Bayesian analysis were employed to quantify this association. Our analysis incorporated 68,803 adverse event reports related to Doxil/Caelyx, Myocet and CDOX. The relative odds ratios (RORs, 95%CI) for febrile neutropenia associated with CDOX, Doxil/Caelyx, and Myocet were 42.45 (41.44; 43.48), 17.53 (16.02; 19.20), and 34.68 (26.63; 45.15) respectively. For cardiotoxicity, they were 38.87(36.41;41.49), 17.96 (14.10; 22.86), and 37.36 (19.34; 72.17). For Palmar-Plantar Erythrodysesthesia (PPE), the RORs were 6.16 (5.69; 6.68), 36.13 (32.60; 40.06), and 19.69 (11.59; 33.44). Regarding onset time, significant differences adverse events including neutropenia, PPE, pneumonia and malignant neoplasm progression. This study indicates that clinical monitoring for symptoms of cardiotoxicity of CDOX and Myocet, and PPE and interstitial lung disease of Doxil should be performed. Additionally, the onset time of febrile neutropenia, malignant neoplasm progression, and pneumonia associated with Doxil and Myocet merits particular attention. Continuous surveillance, risk evaluations, and additional comparative studies between liposomal doxorubicin and CDOX were recommended.
Topics: Humans; Cardiotoxicity; Bayes Theorem; Doxorubicin; Liposomes; Neoplasms; Neutropenia; Pneumonia; Polyethylene Glycols
PubMed: 38429374
DOI: 10.1038/s41598-024-55185-4