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Small (Weinheim An Der Bergstrasse,... Oct 2023Fasting has many health benefits, including reduced chemotherapy toxicity and improved efficacy. It is unclear how fasting affects the tumor microenvironment (TME) and...
Fasting has many health benefits, including reduced chemotherapy toxicity and improved efficacy. It is unclear how fasting affects the tumor microenvironment (TME) and tumor-targeted drug delivery. Here the effects of intermittent (IF) and short-term (STF) fasting are investigated on tumor growth, TME composition, and liposome delivery in allogeneic hepatocellular carcinoma (HCC) mouse models. To this end, mice are inoculated either subcutaneously or intrahepatically with Hep-55.1C cells and subjected to IF for 24 d or to STF for 1 d. IF but not STF significantly slows down tumor growth. IF increases tumor vascularization and decreases collagen density, resulting in improved liposome delivery. In vitro, fasting furthermore promotes the tumor cell uptake of liposomes. These results demonstrate that IF shapes the TME in HCC towards enhanced drug delivery. Finally, when combining IF with liposomal doxorubicin treatment, the antitumor efficacy of nanochemotherapy is found to be increased, while systemic side effects are reduced. Altogether, these findings exemplify that the beneficial effects of fasting on anticancer therapy outcomes go beyond modulating metabolism at the molecular level.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Liposomes; Liver Neoplasms; Intermittent Fasting; Nanomedicine; Tumor Microenvironment; Doxorubicin; Cell Line, Tumor
PubMed: 37376850
DOI: 10.1002/smll.202208042 -
International Journal of Pharmaceutics May 2024Doxorubicin hydrochloride (DOX) is an anticancer agent used in cancer chemotherapy. The purpose of this study was to design nanostructured lipid carriers (NLCs) of DOX...
Doxorubicin hydrochloride (DOX) is an anticancer agent used in cancer chemotherapy. The purpose of this study was to design nanostructured lipid carriers (NLCs) of DOX as smart chemotherapy to improve its photostability and anticancer efficacy. The characteristics of DOX and DOX-loaded NLCs were investigated using UV-Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, particle size, and zeta potential study. The cytotoxicity of DOX was evaluated against three cancer cell lines (HeLa, A549, and CT-26). The particle size and zeta potential were in the range 58.45-94.08 nm and -5.80 mV - -18.27 mV, respectively. The chemical interactions, particularly hydrogen bonding and van der Waals forces, between DOX and the main components of NLCs was confirmed by FTIR. NLCs showed the sustained release profile of DOX. The photostability results revealed that the NLC system improved the photostability of DOX. Cytotoxicity results using the three cell lines showed that all formulations improved the anticancer efficacy of free DOX, and the efficacy was dependent on cell type and particle size. These results suggest that DOX-loaded NLCs are promising chemotherapeutic agents for cancer treatment.
Topics: Doxorubicin; Humans; Drug Carriers; Nanoparticles; Lipids; Cell Line, Tumor; Particle Size; Drug Liberation; Cell Survival; Antibiotics, Antineoplastic; Nanostructures; Drug Stability; HeLa Cells; A549 Cells; Antineoplastic Agents
PubMed: 38537925
DOI: 10.1016/j.ijpharm.2024.124048 -
Journal of Cancer Research and Clinical... Jul 2023Although undergoing conventional chemotherapy significantly improves the prognosis of Osteosarcoma, chemoresistance and failure of therapy is still a significant...
PURPOSE
Although undergoing conventional chemotherapy significantly improves the prognosis of Osteosarcoma, chemoresistance and failure of therapy is still a significant challenge. Furthermore, conventional chemotherapy, like doxorubicin, would upregulate the expression of programmed death-ligand 1 (PD-L1) which caused an immunosuppressive microenvironment and unsatisfied treatment result in Osteosarcoma. Thus, it is urgent to explore a strategy to overcome this disadvantage.
METHODS
Human Osteosarcoma cell line MG63 and mouse Osteosarcoma cell line K7 were included in this study. Subcutaneous tumor model was used by injection of K7 cells in BALB/C mice to test the effect of doxorubicin and sorafenib on tumor growth. PD-L1 expression was tested in vitro (flow cytometry, western blot and PCR) and in vivo (flow cytometry and immunohistochemistry). Proportion of immune cells (CD4, CD8, Tregs, and cytotoxic T lymphocytes) in vivo was analyzed with flow cytometry.
RESULTS
Combination of sorafenib and doxorubicin inhibited tumor growth significantly in vivo. Doxorubicin increased PD-L1 expression in vitro and in vivo, while sorafenib inhibited doxorubicin-induced PD-L1 upregulation in vitro and in vivo. Proportion of interferon-γ-secreting CD8 + T lymphocytes in tumor tissue was increased significantly when sorafenib was combined with doxorubicin, while proportion of CD4, CD8, and Tregs was not significantly changed. Extracellular signal-regulated kinases (ERK) pathway could be one of the key mechanisms by which doxorubicin induced upregulation of PD-L1 in Osteosarcoma cells.
CONCLUSION
Combination of sorafenib and conventional chemotherapeutic reagents is a potent strategy to improve treatment effectiveness by modulating tumor microenvironment in Osteosarcoma through increasing proportion of cytotoxic T lymphocytes.
Topics: Animals; Mice; Humans; Sorafenib; B7-H1 Antigen; Up-Regulation; Mice, Inbred BALB C; Doxorubicin; Osteosarcoma; CD8-Positive T-Lymphocytes; Immunosuppressive Agents; Bone Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 36348018
DOI: 10.1007/s00432-022-04458-4 -
Clinical & Translational Oncology :... Aug 2023Osteosarcoma is a malignant tumor that can present with pain in the bones, joints, and local masses. The incidence is highest in adolescents, and the most common sites...
BACKGROUND
Osteosarcoma is a malignant tumor that can present with pain in the bones, joints, and local masses. The incidence is highest in adolescents, and the most common sites are the distal femur, proximal tibia and proximal humerus metaphyseal. Doxorubicin is the first-line chemotherapeutic agent for the treatment of osteosarcoma, but it has many side effects. Cannabidiol is a non-psychoactive plant cannabinoid cannabinol (CBD) that has been shown to be effective against osteosarcoma; however, the molecular targets and mechanisms of CBD action in osteosarcoma remain unclear.
METHODS
Cell proliferation, migration, invasion and colony formation were analyzed using two drugs alone or in combination to evaluate their inhibitory effects on the malignant characteristics of OS cells. Apoptosis and the cell cycle were detected by flow cytometry. The synergistic inhibitory effect of doxorubicin/cannabidiol on tumors was also detected in nude mouse xenotransplantation models.
RESULTS
Through analysis of two osteosarcoma cell lines, MG63 and U2R, it was found that the cannabidiol/doxorubicin combination treatment synergistically inhibited growth, migration and invasion and induced apoptosis, blocking G2 stagnation in OS cells. Further mechanistic exploration suggests that the PI3K-AKT-mTOR pathway and MAPK pathway play an important role in the synergistic inhibitory effect of the two drugs in osteosarcoma. Finally, in vivo experimental results showed that the cannabidiol/doxorubicin combination treatment significantly reduced the number of tumor xenografts compared to cannabidiol alone or doxorubicin alone.
CONCLUSIONS
Our findings in this study suggest that cannabidiol and doxorubicin have a synergistic anticancer effect on OS cells, and their combined application may be a promising treatment strategy for OS.
Topics: Animals; Mice; Humans; Antineoplastic Agents; Phosphatidylinositol 3-Kinases; Cannabidiol; Cell Line, Tumor; Doxorubicin; Osteosarcoma; Apoptosis; Bone Neoplasms; Cell Proliferation
PubMed: 36848028
DOI: 10.1007/s12094-023-03119-3 -
Bioorganic & Medicinal Chemistry Letters May 2024We developed a model small-molecule drug conjugate (SMDC) that employed doxorubicin as a representative chemotherapeutic targeted to the cell membrane biomarker PSMA...
We developed a model small-molecule drug conjugate (SMDC) that employed doxorubicin as a representative chemotherapeutic targeted to the cell membrane biomarker PSMA (prostate-specific membrane antigen) expressed on prostate cancer cells. The strategy capitalized on the clatherin-mediated internalization of PSMA to facilitate the selective uptake and release of doxorubicin in the target cells. The SMDC was prepared and assessed for binding kinetics, plasma stability, cell toxicity, and specificity towards PSMA expressing prostate cancer cell lines. We observed high affinity of the SMDC for PSMA (IC 5 nM) with irreversible binding, as well as specific effectiveness against PSMA(+) cells. These findings validated the strategy for a small molecule-based approach in targeted cancer therapy.
Topics: Humans; Male; Antigens, Surface; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Glutamate Carboxypeptidase II; Prostatic Neoplasms
PubMed: 38521177
DOI: 10.1016/j.bmcl.2024.129712 -
Epigenetics Dec 2023Doxorubicin (DOX) resistance in breast cancer (BC) poses a huge challenge for the therapeutic effect on BC. Lnc KCNQ1OT1 play crucial roles in chemotherapy resistance....
Doxorubicin (DOX) resistance in breast cancer (BC) poses a huge challenge for the therapeutic effect on BC. Lnc KCNQ1OT1 play crucial roles in chemotherapy resistance. However, the role and mechanism of lnc KCNQ1OT1 in DOX resistance BC have not been investigated, which merits further exploration. Based on MCF-7 and MDA-MB-231 cells, MCF-7/DOX and MDA-MB-231/DOX cells were established using gradient concentrations of DOX. IC50 values and cell viability were determined using MTT. Cell proliferation was investigated by colony formation. Flow cytometry was performed to examine cell apoptosis and cell cycle. Gene expression was examined using qRT-PCR and western blot. The interactions among METTL3, lnc KCNQ1OT1, miR-103a-3p, and MDR1 were validated with MeRIP-qPCR, RIP, and dual-luciferase reporter gene assays. The results showed that Lnc KCNQ1OT1 was highly expressed in DOX-resistant BC cells, and lnc KCNQ1OT1 depletion could enhance DOX sensitivity in BC cells and DOX-resistant BC cells. Besides, lnc KCNQ1OT1 was modulated by MELLT3 in the manner of mA modification. MiR-103a-3p could interact with lnc KCNQ1OT1 and MDR1. Overexpression of MDR1 abolished the impacts of lnc KCNQ1OT1 depletion on DOX resistance in BC. In conclusion, our results unveiled that in BC cells and DOX-resistant BC cells, lnc KCNQ1OT1 could be mediated by METTL3 through mA modification to elevate and stabilize its expression, further inhibiting miR-103a-3p/MDR1 axis to promote DOX resistance, which might provide novel thought to overcome DOX resistance in BC.
Topics: Humans; Female; Breast Neoplasms; MicroRNAs; DNA Methylation; Cell Proliferation; Doxorubicin; Methyltransferases
PubMed: 37243702
DOI: 10.1080/15592294.2023.2217033 -
Bioorganic & Medicinal Chemistry Letters Mar 2024Hydrogen sulfide (HS) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (HS) donors by connecting sugar...
Hydrogen sulfide (HS) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (HS) donors by connecting sugar moieties (including glucose, galactose and mannose) to COS donors via a self-immolative spacer. In the presence of corresponding glycosidases, HS was gradually released from these donors in PBS buffer with releasing efficiencies from 36 to 67 %. HS release was also detected by HS probe WSP-1 after treatment HepG2 cells with Man1. Cytotoxicities of these glycosylated HS donors were evaluated against HepG2 by MTT assay. Among them, Man1 and Man2 exhibited an obvious reduction of cell viability in HepG2 cells, with cell viability as 37.6 % for 80 μM of Man. Consistently, significant apoptosis was observed in HepG2 cells after treatment with Man1 and Man2. Finally, We evaluated the potential of Man1 for combination therapy with doxorubicin. A synergistic effect was observed between Man1 and Doxorubicin in HepG2 and Hela cells. All these results indicated glycosidase-activated HS donorshave promising potential for cancer therapy.
Topics: Humans; HeLa Cells; Hydrogen Sulfide; Sulfur Oxides; Doxorubicin; Glycoside Hydrolases
PubMed: 38316370
DOI: 10.1016/j.bmcl.2024.129644 -
Leukemia & Lymphoma 2023Follicular lymphoma (FL) is a common, indolent small B-cell lymphoma. While the Follicular Lymphoma International Prognostic Index is widely used, reliable prognostic...
Follicular lymphoma (FL) is a common, indolent small B-cell lymphoma. While the Follicular Lymphoma International Prognostic Index is widely used, reliable prognostic and predictive biomarkers are needed. A recent study suggested that architectural patterns of CD10, BCL6, and Ki67 expression may correlate with progression-free survival (PFS) in FL patients treated with chemotherapy-free regimens. We examined the prognostic and predictive utility of architectural patterns of CD10, BCL6, Ki67, and FOXP1 in 90 patients treated with immunochemotherapy (bendamustine-rituximab [BR] and R-cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]). We found that high follicular Ki67 (≥30%) was associated with longer PFS in the subgroup of patients treated with R-CHOP but not among those treated with BR. Validation of this biomarker may support routine use of Ki67 as a predictive marker in FL.
Topics: Humans; Rituximab; Vincristine; Lymphoma, Follicular; Prednisone; Ki-67 Antigen; Treatment Outcome; Cyclophosphamide; Doxorubicin; Bendamustine Hydrochloride; Cell Proliferation; Antineoplastic Combined Chemotherapy Protocols; Repressor Proteins; Forkhead Transcription Factors
PubMed: 37226602
DOI: 10.1080/10428194.2023.2214651 -
Small (Weinheim An Der Bergstrasse,... Sep 2023Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting...
Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane-bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active-targeting nanoparticles to overcome receptor-binding barriers. Herein, the Hsp70-targeting and acid-triggered self-assembled gold nanoparticles (D-A-DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D-A-DA/TPP formed aggregates to prolong retention, improve receptor-binding efficiency and facilitate acid-responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD-1 checkpoint blockade further activate T cells and provokes robust anti-tumor immunity. The results showed that D-A-DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D-A-DA/TPP plus PD-1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size-tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD-1 checkpoint blockade to achieve chemo-immunotherapy.
Topics: Humans; Programmed Cell Death 1 Receptor; Gold; Metal Nanoparticles; Glioma; Doxorubicin; Nanoparticles; Cell Line, Tumor
PubMed: 37222118
DOI: 10.1002/smll.202300570 -
Journal of Controlled Release :... May 2024The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge,...
The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel "Y"-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery.
Topics: Animals; Endoplasmic Reticulum Chaperone BiP; Glioma; Doxorubicin; Humans; Mice, Nude; Cell Line, Tumor; Drug Delivery Systems; Brain Neoplasms; Peptides; Blood-Brain Barrier; Heat-Shock Proteins; Antibiotics, Antineoplastic; Mice, Inbred BALB C; Receptors, Dopamine D2; Mice; Male
PubMed: 38583575
DOI: 10.1016/j.jconrel.2024.04.011