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1.
Mol Cancer ; 21(1): 37, 2022 02 07.
Article in English | MEDLINE | ID: mdl-35130920

ABSTRACT

PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.


Subject(s)
Antineoplastic Agents , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Carcinoma, Transitional Cell/drug therapy , Cell Line, Tumor , Cell Proliferation , Cisplatin/pharmacology , Cisplatin/therapeutic use , Drug Resistance, Neoplasm/genetics , Heterogeneous-Nuclear Ribonucleoprotein U , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology
2.
Am J Vet Res ; 83(6)2022 May 08.
Article in English | MEDLINE | ID: mdl-35524959

ABSTRACT

OBJECTIVE: To determine the in vitro effects of the proteasome inhibitor bortezomib in feline injection site sarcoma (FISS) cell lines. SAMPLE: In vitro cultures of the FISS cell lines Ela-1, Hamilton, and Kaiser. PROCEDURES: Cells were treated with increasing doses of bortezomib or vehicle alone (dimethyl sulfoxide) and evaluated for cell viability via an adenosine triphosphate concentration assay, proteasome activity via a commercially available proteasome assay, accumulation of ubiquitinated proteins via Western blot, and apoptosis via flow cytometry. RESULTS: All 3 cell lines were sensitive to bortezomib with a 50% inhibitory concentration after 48 hours of treatment at 17.46 nM (95% CI, 15.47 to 19.72 nM) for Ela-1, 19.48 nM (95% CI, 16.52 to 23.00 nM) for Hamilton, and 21.38 nM (95% CI, 19.24 to 23.78 nM) for Kaiser. In the Ela-1 cell line, 20 nM bortezomib inhibited 20S proteasome activity by 90.9% compared with the vehicle-only control. In the Kaiser cell line, 20 nM bortezomib decreased 20S proteasome activity by 70%, compared with the untreated vehicle-only control. Last, treatment with bortezomib (25 and 40 nM) resulted in statistically significant decreases in viable cells accompanied by a statistically significant increase in apoptotic cells. CLINICAL RELEVANCE: Treatment options for FISS, especially nonresectable FISS, are currently very limited. These results support further investigation of bortezomib either alone or in combination with other treatments in such cases.


Subject(s)
Antineoplastic Agents , Cat Diseases , Sarcoma , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Boronic Acids/pharmacology , Bortezomib/pharmacology , Cats , Cell Line, Tumor , Proteasome Endopeptidase Complex/pharmacology , Pyrazines/pharmacology , Sarcoma/veterinary
3.
Int J Biol Sci ; 18(7): 2898-2913, 2022.
Article in English | MEDLINE | ID: mdl-35541893

ABSTRACT

Although triple-negative breast cancer (TNBC) is the most refractory subtype among all breast cancers, it has been shown to have higher immune infiltration than other subtypes. We identified the marine-derived small molecule MHO7, which acts as a potent immunogenic cell death (ICD) inducer through the endoplasmic reticulum (ER) stress-C/EBP-homologous protein (CHOP) pathway, to treat TNBC. MHO7 exerted cytostatic and cytotoxic effects on TNBC cells at an IC50 of 0.96-1.75 µM and suppressed tumor growth with an approximately 80% inhibition rate at a dose of 60 mg/kg. In 4T1 cell tumor-bearing mice, 30 mg/kg MHO7 inhibited pulmonary metastasis with an efficacy of 70.26%. Transcriptome analyses revealed that MHO7 changed the transcription of genes related to ribosome and protein processes in the ER. MHO7 also triggered reactive oxygen species (ROS) generation and attenuated glutathione (GSH) levels, which caused excessive oxidative stress and ER stress via the PERK/eIF2α/AFT4/CHOP pathway and led to cell apoptosis. ER stress and ROS production facilitated the release of ICD-related danger-associated molecular patterns (DAMPs) from TNBC cells, which activated the immune response in vivo, as indicated by the release of antitumor cytokines such as IL-6, IL-1ß, IFN-γ, and TNF-α, increases in CD86+ and MHC-II dendritic cells and CD4+ and CD8+ T cells and a decrease in regulatory T cells (Tregs). These results reveal that MHO7 triggers an aggressive stress response to amplify tumor immunogenicity and induce a robust immune response. This synergistic effect inhibits primary breast cancer growth and spontaneous metastasis in TNBC, providing a new strategy for TNBC treatment.


Subject(s)
Antineoplastic Agents , Triple Negative Breast Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Endoplasmic Reticulum Stress , Humans , Immunogenic Cell Death , Mice , Reactive Oxygen Species/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism
4.
Int J Biol Sci ; 18(7): 2994-3005, 2022.
Article in English | MEDLINE | ID: mdl-35541904

ABSTRACT

Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo, daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical cancer growth in vitro and in vivo.


Subject(s)
Antineoplastic Agents , Uterine Cervical Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Line, Tumor , Cell Proliferation , Ceramides/metabolism , Female , Humans , Mammals/metabolism , Mice , Mice, Nude , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Uterine Cervical Neoplasms/drug therapy
5.
Int J Biol Sci ; 18(7): 2684-2702, 2022.
Article in English | MEDLINE | ID: mdl-35541921

ABSTRACT

Macroautophagy/autophagy is the process of self-digestion through the lysosomes; it disassembles unnecessary or dysfunctional long-lived proteins and damaged organelles for the recycling of biomacromolecules. Unfortunately, cancer cells can hijack this mechanism to survive under metabolic stress or develop drug resistance during chemotherapy. Increasing evidence indicates that the combination of autophagy inhibition and chemotherapy is a promising cancer treatment strategy. However, effective autophagy inhibitors with satisfied potency, bioavailability, and clearly-defined drug targets are still rare. Here, we report the identification of a potent autophagy inhibitor toosendanin which can effectively block autophagosome maturation, causing the accumulation of autophagy substrates in multiple cancer cells. Toosendanin did not inhibit the fusion process between autophagosome and lysosome but elevated lysosomal pH and impaired lysosomal enzymes activity. Using rat liver lysosome fraction and purified yeast V-ATPase, we found that toosendanin directly inhibited V-ATPase activity. By applying cellular thermal shift assay (CETSA), immunoprecipitation-coupled LC-MS/MS analysis, and biotin-toosendanin pull-down assay, we confirmed the direct binding between toosendanin and V-ATPase. Furthermore, toosendanin blocked chemotherapy-induced protective autophagy in cultured cancer cells and xenograft tumor tissues to significantly enhance anti-cancer activity. These results suggest that toosendanin has the potential to be developed into an anti-cancer drug by blocking chemotherapy-induced protective autophagy.


Subject(s)
Antineoplastic Agents , Neoplasms , Vacuolar Proton-Translocating ATPases , Adenosine Triphosphatases/metabolism , Animals , Antineoplastic Agents/pharmacology , Autophagy , Chromatography, Liquid , Humans , Neoplasms/drug therapy , Rats , Tandem Mass Spectrometry , Triterpenes , Vacuolar Proton-Translocating ATPases/metabolism , Vacuolar Proton-Translocating ATPases/pharmacology
6.
Oncol Rep ; 47(6)2022 Jun.
Article in English | MEDLINE | ID: mdl-35506458

ABSTRACT

Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany in 1971 and approved by the US Food and Drug Administration in 2008 for treatment of chronic lymphocytic leukemia and indolent B­cell non­Hodgkin lymphoma. Considering its beneficial properties in the therapy of relapsed or refractory hematological malignancies, synergistic effects with other antineoplastic agents and increasing recent reports on its immunomodulatory effects, bendamustine has once again gained its justified attention. The uniqueness of bendamustine­mediated effects should be observed keeping in mind its distinctive structure with structural similarities to both alkylating agents and purine analogs. In the present review, the current knowledge on the use of bendamustine in oncology, its pharmacokinetics, mechanism of action and toxicity was summarized. In addition, its immune­modulating effects that have not been fully elucidated so far are emphasized, hoping to encourage further investigations of this unique drug.


Subject(s)
Antineoplastic Agents , Leukemia, Lymphocytic, Chronic, B-Cell , Lymphoma, B-Cell , Nitrogen Mustard Compounds , Antineoplastic Agents/pharmacology , Bendamustine Hydrochloride/pharmacology , Bendamustine Hydrochloride/therapeutic use , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, B-Cell/drug therapy , Nitrogen Mustard Compounds/chemistry , Nitrogen Mustard Compounds/pharmacology , Nitrogen Mustard Compounds/therapeutic use
7.
Drug Deliv ; 29(1): 1447-1456, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35532152

ABSTRACT

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.


Subject(s)
Antineoplastic Agents , Arsenicals , Arsenites , Nanoparticles , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Arsenicals/pharmacology , Arsenites/pharmacology , Cell Line, Tumor , Drug Carriers/pharmacology , Drug Synergism , Oxides , Sevelamer/pharmacology
8.
Clin Transl Med ; 12(5): e825, 2022 May.
Article in English | MEDLINE | ID: mdl-35522895

ABSTRACT

AIMS: MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented. METHODS AND RESULTS: We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition. CONCLUSION: We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Transcription Factors , Adenosine Triphosphatases/genetics , Antineoplastic Agents/pharmacology , Autophagy/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Female , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/genetics , Humans , Oncogene Proteins
9.
BMC Cancer ; 22(1): 521, 2022 May 09.
Article in English | MEDLINE | ID: mdl-35534815

ABSTRACT

BACKGROUND: Tumor resistance is a global challenge for tumor treatment. Cancer stem cells (CSCs) are the main population of tumor cells for drug resistance. We have reported that high aldehyde dehydrogenase (ALDH) activity represents a functional marker for cervical CSCs. Here, we aimed at disulfiram (DSF), an ALDH inhibitor, that has the potential to be used for cervical cancer treatment. METHODS: MTT assay, western blot, vector construction and transfection, cell sorting and in vivo anti-tumor assays were performed using cervical cancer cell lines SiHa and HeLa. Cell cycle distribution and cell apoptosis were carried out by flow cytometry. The cytotoxicity of DSF was detected by MTT assay and cervical cancer xenograft models. RESULTS: DSF was cytotoxic to cervical cancer cell lines in a copper (Cu)-dependent manner. Disulfiram/copper (DSF/Cu) complex induced deregulation of S-phase and inhibited the expression of stemness markers in cervical cancer cells. Furthermore, DSF/Cu could also reduce the cancer stem cell-like LGR5+ cells which lead to cisplatin resistance in cervical cancer cells. DSF/Cu complex had the greater antitumor efficacy on cervical cancer than cisplatin in vitro and in vivo. CONCLUSION: Our findings indicate that the cytotoxicity of DSF/Cu complex may be superior to cisplatin because of targeting LGR5-positive cervical cancer stem-like cells in cervical cancer. Thus, the DSF/Cu complex may represent a potential therapeutic strategy for cervical cancer patients.


Subject(s)
Antineoplastic Agents , Copper , Disulfiram , Uterine Cervical Neoplasms , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cisplatin/pharmacology , Copper/pharmacology , Disulfiram/pharmacology , Female , Humans , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Receptors, G-Protein-Coupled/metabolism , Uterine Cervical Neoplasms/pathology
10.
J Biomed Sci ; 29(1): 29, 2022 May 09.
Article in English | MEDLINE | ID: mdl-35534851

ABSTRACT

BACKGROUND: Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC. METHODS: In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts. RESULTS: Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone. CONCLUSIONS: These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.


Subject(s)
Antineoplastic Agents , Biological Products , Flavonoids , Prostatic Neoplasms, Castration-Resistant , Androgens/pharmacology , Androgens/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biological Products/pharmacology , Biological Products/therapeutic use , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm , Flavonoids/pharmacology , Glycolates , Glycols/pharmacology , Glycols/therapeutic use , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , Jumonji Domain-Containing Histone Demethylases/pharmacology , Male , Nitriles/pharmacology , Nitriles/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Receptors, Androgen/therapeutic use
11.
Elife ; 112022 May 10.
Article in English | MEDLINE | ID: mdl-35535493

ABSTRACT

Hundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs.


Subject(s)
Antineoplastic Agents , Short Chain Dehydrogenase-Reductases , Antineoplastic Agents/pharmacology , Endoplasmic Reticulum Stress , Humans , Lipids , Unfolded Protein Response
12.
Methods Mol Biol ; 2429: 501-507, 2022.
Article in English | MEDLINE | ID: mdl-35507184

ABSTRACT

Cancer stem cells (CSCs) are a small subpopulation of self-renewing cancer cells that are present within tumors. CSCs possess tumor initiation potential as well as the ability to resist toxic compounds and chemotherapeutic agents through the upregulation of drug efflux transporters, DNA repair pathways, and survival cascades. Accumulating evidence suggests that CSCs are responsible for tumor relapse and resistance to chemotherapeutic agents and that targeting CSCs is critical to inhibition of cancer progression. Therefore, isolation and characterization of CSCs is important in studying tumor initiation and progression. In this chapter, we provide a detailed method for the identification and isolation of CSCs.


Subject(s)
Antineoplastic Agents , Neoplasm Recurrence, Local , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Humans , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/metabolism
13.
Proc Natl Acad Sci U S A ; 119(19): e2123483119, 2022 May 10.
Article in English | MEDLINE | ID: mdl-35507878

ABSTRACT

SignificanceA target-agnostic approach that harnesses the human antitumor immune response to find potential anticancer lead antibodies and their targets was used to generate ATRC-101, an engineered version of a tumor-targeting antibody identified from a patient with non-small cell lung cancer experiencing an ongoing antitumor immune response. ATRC-101 is an antibody that targets an extracellular, tumor-specific ribonucleoprotein complex. Here, we describe the extracellular binding of this complex and antitumor activity of ATRC-101 in murine models. Preclinical data suggest a mechanism of action in which ATRC-101 activates myeloid cells of the innate immune system, leading to an adaptive immune response that yields its antitumor activity. These data have led to an ongoing phase 1 trial in patients with advanced solid tumors.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Neoplasms , Adaptive Immunity , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Immunity, Innate , Mice , Neoplasms/pathology
14.
Methods Mol Biol ; 2451: 49-58, 2022.
Article in English | MEDLINE | ID: mdl-35505009

ABSTRACT

Numerous cancer models have been developed to investigate the effects of mechanical stress on the biology of cells. Here we describe a protocol to fabricate a perfusion model to culture 3-dimensional (3D) ovarian cancer nodules under constant flow. The modular design of this model allows for a wide range of treatment regimens and combinations, including PDT and chemotherapy. Finally, methods for a number of readouts are detailed, allowing researchers to investigate a variety of biological and cytotoxic parameters related to mechanical stress and therapeutic modalities.


Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Photochemotherapy , Antineoplastic Agents/pharmacology , Female , Humans , Ovarian Neoplasms/drug therapy , Perfusion/methods
15.
J Adv Res ; 37: 279-290, 2022 03.
Article in English | MEDLINE | ID: mdl-35499049

ABSTRACT

Introduction: Cancer is a big challenge of the 21 century, whose defeat requires efficient antitumor drugs. Objectives: The paper aims to investigate the synergistic effect of two structural building blocks, phenothiazine and poly(ethylene glycol), towards efficient antitumor drugs. Methods: Two PEGylated phenothiazine derivatives were synthetized by attaching poly(ethylene glycol) of 550 Da to the nitrogen atom of phenothiazine by ether or ester linkage. Their antitumor activity has been investigated on five human tumour lines and a mouse tumor line as well, by determination of IC50. The in vivo toxicity was determined by measuring the LD50 in BALB/c mice by the sequential method and the in vivo antitumor potential was measured by the tumours growth test. The antitumor mechanism was investigated by complexation studies of zinc and magnesium ions characteristic to the farnesyltransferase enzyme, by studies of self-aggregation in the cells proximity and by investigation of the antitumor properties of the acid species resulted by enzymatic cleavage of the PEGylated derivatives. Results: The two compounds showed antitumor activity, with IC50 against mouse colon carcinoma cell line comparable with that of the traditional antitumor drugs 5-Fluorouracil and doxorubicin. The phenothiazine PEGylation resulted in a significant toxicity diminishing, the LD50 in BALB/c mice increasing from 952.38 up to 1450 mg/kg, in phenothiazine equivalents. Both compounds inflicted a 92% inhibition of the tumour growth for doses much smaller than LD50. The investigation of the possible tumour inhibition mechanism suggested the nanoaggregate formation and the cleavage of ester bonds as key factors for the inhibition of cancer cell proliferation and biocompatibility improvement. Conclusion: Phenothiazine and PEG building blocks have a synergetic effect working for both tumour growth inhibition and biocompatibility improvement. All these findings recommend the PEGylated phenothiazine derivatives as a valuable workbench for a next generation of antitumor drugs.


Subject(s)
Antineoplastic Agents , Antipsychotic Agents , Animals , Antineoplastic Agents/pharmacology , Esters , Farnesyltranstransferase , Mice , Phenothiazines/pharmacology , Polyethylene Glycols
16.
BMC Cancer ; 22(1): 512, 2022 May 07.
Article in English | MEDLINE | ID: mdl-35525914

ABSTRACT

BACKGROUND: Indian natural products have been anecdotally used for cancer treatment but with limited efficacy. To better understand their mechanism, we examined the publicly available data for the activity of Indian natural products in the NCI-60 cell line panel. METHODS: We examined associations of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 75 compounds derived from Indian plant-based natural products. We analyzed expression measures for annotated transcripts, lncRNAs, and miRNAs, and protein-changing single nucleotide variants in cancer-related genes. We also examined the similarities between cancer cell line response to Indian natural products and response to reference anti-tumor compounds recorded in a U.S. National Cancer Institute (NCI) Developmental Therapeutics Program database. RESULTS: Hierarchical clustering based on cell line response measures identified clustering of Phyllanthus and cucurbitacin products with known anti-tumor agents with anti-mitotic mechanisms of action. Curcumin and curcuminoids mostly clustered together. We found associations of response to Indian natural products with expression of multiple genes, notably including SLC7A11 involved in solute transport and ATAD3A and ATAD3B encoding mitochondrial ATPase proteins, as well as significant associations with functional single nucleotide variants, including BRAF V600E. CONCLUSION: These findings suggest potential mechanisms of action and novel associations of in vitro response with gene expression and some cancer-related mutations that increase our understanding of these Indian natural products.


Subject(s)
Antineoplastic Agents , Biological Products , Neoplasms , ATPases Associated with Diverse Cellular Activities , Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Cell Line, Tumor , Humans , Membrane Proteins , Mitochondrial Proteins , National Cancer Institute (U.S.) , Neoplasms/drug therapy , Neoplasms/genetics , Nucleotides , Pharmacogenetics , United States
17.
F1000Res ; 11: 237, 2022.
Article in English | MEDLINE | ID: mdl-35529278

ABSTRACT

B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Recent studies have demonstrated that this protein is frequently overactivated in human cancers, especially when it bears activating mutations. In recent years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to such ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance. Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good premises. However, several limitations could still be envisioned for these compounds, according to recent literature data. Besides, increased attentions have recently arisen around approaches based on the design of allosteric modulators, polypharmacology, PROTACs and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, novel valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, the most recent approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies.


Subject(s)
Antineoplastic Agents , Melanoma , Adenosine Triphosphate , Antineoplastic Agents/pharmacology , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics
18.
Drug Deliv ; 29(1): 1384-1397, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35532120

ABSTRACT

Colorectal cancer (CRC) remains the third cause of cancer-related mortality in Western countries, metastases are the main cause of death. CRC treatment remains limited by systemic toxicity and chemotherapy resistance. Therefore, nanoparticle-mediated delivery of cytotoxic agents selectively to cancer cells represents an efficient strategy to increase the therapeutic index and overcome drug resistance. We have developed the T22-PE24-H6 therapeutic protein-only nanoparticle that incorporates the exotoxin A from Pseudomonas aeruginosa to selectively target CRC cells because of its multivalent ligand display that triggers a high selectivity interaction with the CXCR4 receptor overexpressed on the surface of CRC stem cells. We here observed a CXCR4-dependent cytotoxic effect for T22-PE24-H6, which was not mediated by apoptosis, but instead capable of inducing a time-dependent and sequential activation of pyroptotic markers in CRC cells in vitro. Next, we demonstrated that repeated doses of T22-PE24-H6 inhibit tumor growth in a subcutaneous CXCR4+ CRC model, also through pyroptotic activation. Most importantly, this nanoparticle also blocked the development of lymphatic and hematogenous metastases, in a highly aggressive CXCR4+ SW1417 orthotopic CRC model, in the absence of systemic toxicity. This targeted drug delivery approach supports for the first time the clinical relevance of inducing GSDMD-dependent pyroptosis, a cell death mechanism alternative to apoptosis, in CRC models, leading to the selective elimination of CXCR4+ cancer stem cells, which are associated with resistance, metastases and anti-apoptotic upregulation.


Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Phosphate-Binding Proteins , Pore Forming Cytotoxic Proteins , Pyroptosis , Receptors, CXCR4 , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Drug Delivery Systems , Humans , Neoplasm Metastasis/prevention & control , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/metabolism , Receptors, CXCR4/metabolism , Receptors, CXCR4/therapeutic use , Signal Transduction
19.
Acta Biochim Biophys Sin (Shanghai) ; 54(3): 279-291, 2022 Mar 25.
Article in English | MEDLINE | ID: mdl-35538038

ABSTRACT

With the development of precision medicine, the efficiency of tumor treatment has been significantly improved. More attention has been paid to targeted therapy and immunotherapy as the key to precision treatment of cancer. Targeting epidermal growth factor receptor (EGFR) has become one of the most important targeted treatments for various cancers. Comparing with traditional chemotherapy drugs, targeting EGFR is highly selective in killing tumor cells with better safety, tolerability and less side effect. In addition, tumor immunotherapy has become the fourth largest tumor therapy after surgery, radiotherapy and chemotherapy, especially immune checkpoint inhibitors. However, these treatments still produce a certain degree of drug resistance. Non-coding RNAs (ncRNAs) were found to play a key role in carcinogenesis, treatment and regulation of the efficacy of anticancer drugs in the past few years. Therefore, in this review, we aim to summarize the targeted treatment of cancers and the functions of ncRNAs in cancer treatment.


Subject(s)
Antineoplastic Agents , Neoplasms , RNA, Long Noncoding , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , ErbB Receptors , Humans , Immunotherapy , Neoplasms/drug therapy , Neoplasms/genetics , RNA, Long Noncoding/genetics , RNA, Untranslated/genetics , RNA, Untranslated/therapeutic use
20.
BMC Bioinformatics ; 23(1): 163, 2022 May 05.
Article in English | MEDLINE | ID: mdl-35513784

ABSTRACT

BACKGROUND: To reduce drug side effects and enhance their therapeutic effect compared with single drugs, drug combination research, combining two or more drugs, is highly important. Conducting in-vivo and in-vitro experiments on a vast number of drug combinations incurs astronomical time and cost. To reduce the number of combinations, researchers classify whether drug combinations are synergistic through in-silico methods. Since unstructured data, such as biomedical documents, include experimental types, methods, and results, it can be beneficial extracting features from documents to predict anti-cancer drug combination synergy. However, few studies predict anti-cancer drug combination synergy using document-extracted features. RESULTS: We present a novel approach for anti-cancer drug combination synergy prediction using document-based feature extraction. Our approach is divided into two steps. First, we extracted documents containing validated anti-cancer drug combinations and cell lines. Drug and cell line synonyms in the extracted documents were converted into representative words, and the documents were preprocessed by tokenization, lemmatization, and stopword removal. Second, the drug and cell line features were extracted from the preprocessed documents, and training data were constructed by feature concatenation. A prediction model based on deep and machine learning was created using the training data. The use of our features yielded higher results compared to the majority of published studies. CONCLUSIONS: Using our prediction model, researchers can save time and cost on new anti-cancer drug combination discoveries. Additionally, since our feature extraction method does not require structuring of unstructured data, new data can be immediately applied without any data scalability issues.


Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Computational Biology/methods , Drug Combinations , Humans , Machine Learning , Neoplasms/drug therapy
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