• Nile Blue analogue
• anticancer drug
• benzo[a]phenoxazine
• breast cancer
• colorectal cancer
• lysosome membrane permeabilization

• Humans
• Lysosomes/drug effects
• Lysosomes/metabolism
• Oxazines/pharmacology
• Oxazines/therapeutic use
• Antineoplastic Agents/pharmacology
• Cell Proliferation/drug effects
• Cell Line, Tumor
• Reactive Oxygen Species/metabolism
• MCF-7 Cells
• Cell Survival/drug effects
• Cell Movement/drug effects

• COVID/BD/151978/2021 Fundação para a Ciência e Tecnologia
• UID/BIA/04050/2020 Fundação para a Ciência e Tecnologia
• UID/QUI/0686/2021 Fundação para a Ciência e Tecnologia
• PTDC/QUIQIN/28662/2017 Fundação para a Ciência e Tecnologia
• SFRH/BD/133207/2017 Fundação para a Ciência e Tecnologia

• TET family genes
• drug sensitivity
• pan-cancer analysis
• therapeutic target
• tumor microenvironment

• National Natural Science Foundation of China
• Natural Science Foundation of Tianjin Municipality
• Natural Science Foundation of Beijing Municipality

• MCTS
• PGE2
• drug screen
• mPGES-1
• neuroblastoma
• spheroids

• Humans
• Prostaglandin-E Synthases
• Drug Resistance, Neoplasm
• Spheroids, Cellular
• Neuroblastoma/drug therapy
• Drug Discovery/methods

• PR2018-0055 Barncancerfonden
• PR2020-0104 Barncancerfonden
• TJ2017-0040 Barncancerfonden
• 19-0183 Cancerfonden
• 171073 Radiumhemmets Forskningsfonder
• 2021-03420 Vetenskapsrådet
• Barncancerfonden
• Cancerfonden
• Radiumhemmets Forskningsfonder
• Vetenskapsrådet

• ABC transporters
• ABCC1/MRP1
• ABCC10/MRP7
• SSRI family
• cancer
• drug resistance

• K562/ADM
• SLC25A40
• buthionine sulfoximine
• drug resistance
• glutathione

• Humans
• Antineoplastic Agents/pharmacology
• ATP Binding Cassette Transporter, Subfamily B/genetics
• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Doxorubicin/pharmacology
• Drug Resistance
• Drug Resistance, Neoplasm
• K562 Cells
• Leukemia, Myeloid

• Bufalin
• cinobufacini
• drug resistance
• review
• tumor

Colorectal cancer (CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence, and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer; thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages III and IV. Despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors (smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus, the individual mechanisms involved in developing the CRC microenvironment, their causes, and their consequences need to be understood from a genetic and immunological perspective. This review highlighted the importance of altering the immune response in CRC. It focused on drugs that may modulate the immune response and show specific efficacy and contrasted with evidence that immunosuppression or the promotion of the immune response is the answer to generating effective treatments with combined chemotherapeutic drugs.

• Colorectal cancer
• Immunotherapy checkpoint inhibitors
• Chemotherapy
• Immunotherapy
• Immune response

• drug-delivery
• fluorescently labeled MSNs
• functionalized MSNs
• mesoporous silica nanoparticles
• multidrug resistance

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents/therapeutic use
• Doxorubicin
• Drug Carriers/pharmacology
• Drug Delivery Systems/methods
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Nanoparticles/ultrastructure
• Neoplasms/drug therapy
• Porosity
• Silicon Dioxide/pharmacology

• the Hungarian Government and the European Union

• Aldo-keto reductase 1C3
• breast cancer
• chemoresistance
• cisplatin
• glutathione
• proteasome

• Nodal
• P-gp
• RCC
• p65
• transcription

This study investigated a nanoparticle drug delivery system to reverse multidrug resistance (MDR) and assessed its anticancer efficacy in hepatocellular carcinoma (HCC).

Docosahexaenoic acid (DHA) was used as the functional excipient and doxorubicin (DOX) as the chemotherapeutic drug to synthesize DOX nanoparticles (DOX-nano). The human HCC cell line HepG2 was used for experiments. HepG2/DOX, HepG2+DOX, HepG2+DOX-nano, HepG2/DOX+DOX, and HepG2/DOX+DOX-nano groups cells were treated with DOX or DOX-nano (5 μg/mL). Nude mice bearing a HepG2/DOX xenograft were divided into model, DOX, vector-nano, and DOX-nano groups and injected with saline, DOX reagent, vector-nano, and DOX-nano (2 mg/kg), respectively. Next, cytotoxicity, cellular uptake, cell apoptosis and migration, fluorescence imaging, TUNEL assay, and tumor inhibition effects were assessed in vitro and in vivo. Furthermore, expression of MDR-related proteins was also detected using western blotting.

Fluorescence imaging showed that the DOX uptake in the DOX-nano-treated group was the strongest in the HCC cells or tumors. Cell apoptosis was significantly increased in DOX-nano-treated HepG2/DOX cells and tumors, and cell migration was significantly inhibited in the DOX-nano-treated HepG2/DOX cells compared with the other groups. The tumor inhibitory rate in DOX-nano-injected tumors was also significantly higher than in other groups. The expression of breast cancer resistance protein, B-cell lymphoma 2, lung resistance protein, multidrug resistance protein, and protein kinase C alpha was significantly decreased in DOX-nano-treated HepG2/DOX cells and xenograft tumors. Significantly better antitumor and MDR-reversing effects were also observed in the HepG2+DOX group compared with the HepG2/DOX group.

This study revealed the potential efficacy of a DOX-nano drug delivery system for the treatment of HCC, using HepG2/DOX cells and nude mice bearing HepG2/DOX xenografts.

• 5Z,9Z-dienoic acids
• anticancer activity
• apoptosis
• cell signaling
• cross-cyclomagnesiation
• lithocholic acid

• M2 muscarinic receptors
• cisplatin
• doxorubicin
• drug resistance
• efflux pumps
• neuroblastoma

• ATP-Binding Cassette Transporters/genetics
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Arecoline/administration & dosage
• Arecoline/analogs & derivatives
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cisplatin/administration & dosage
• Doxorubicin/administration & dosage
• Drug Resistance, Neoplasm
• Gene Expression/drug effects
• Humans
• Neuroblastoma/drug therapy
• Neuroblastoma/metabolism
• Neuroblastoma/pathology
• Receptor, Muscarinic M2/agonists
• Receptor, Muscarinic M2/genetics

• MSNs
• Nanocarriers
• dendrimers
• nanotubes
• quantum dots.
• specificity

Soft tissue sarcomas (STS) are a rare group of mesenchymal solid tumors with heterogeneous genetic profiles and clinical features. Systemic chemotherapy is the backbone treatment for advanced STS; however, STS frequently acquire resistance to standard therapies, which highlights the need to improve treatments and identify novel therapeutic targets. Increases in the knowledge of the molecular pathways that drive sarcomas have brought to light different molecular alterations that cause tumor initiation and progression. These findings have triggered a breakthrough of targeted therapies that are being assessed in clinical trials. Cancer stem cells (CSCs) exhibit mesenchymal stem cell (MSC) features and represent a subpopulation of tumor cells that play an important role in tumor progression, chemotherapy resistance, recurrence and metastasis. In fact, CSCs phenotypes have been identified in sarcomas, allied to drug resistance and tumorigenesis. Herein, we will review the published evidence of CSCs in STS, discussing the molecular characteristic of CSCs, the commonly used isolation techniques and the new possibilities of targeting CSCs as a way to improve STS treatment and consequently patient outcome.

• cancer stem cells
• chemotherapy resistance
• genetic and epigenetic plasticity
• soft-tissue sarcoma
• stemness
• tumor heterogeneity
• tumor-initiating cells

• Multidrug resistance
• Nanoprobe
• P-glycoprotein
• Telomerase
• Theranostic

• drug resistance
• drug response
• multiple myeloma
• treatment

Doxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer. However, chronic cardiotoxicity and multidrug resistance limit the chemotherapeutic use of DOX.

This study aimed to evaluate the capability of calcium channel blocker diltiazem (DIL) to reverse DOX resistance in breast cancer MCF-7 cells and to confer protection against DOX-induced cardiotoxicity in Wistar rats. For this purpose, we explored the effects of DOX on cell cycle phase distribution and expression of ABCB1, FOXO3a, and p53 genes in the presence and absence of DIL (20 μg/ml) and studied the ability of DIL to prevent DOX-induced cardiotoxicity after a single injection of DOX (15 mg/kg) in male Wister rats.

We found that compared with DOX alone treatment, DIL + DOX treatment down regulated the ABCB1 gene expression by > fourfold but up regulated the FOXO3a and p53 genes expression by 1.5 fold. DIL treatment conferred protection against DOX-induced cardiotoxicity, as indicated by a decrease in the levels of the cardiac enzyme creatine kinase MB and malondialdehyde and an increase in the total antioxidant capacity and glutathione peroxidase levels. These biochemical results were further confirmed by the histopathological investigation of cardiac cells, which showed normal cardiac cells with central vesicular nuclei and prevention of DOX-induced disruption of normal cardiac architecture in the DIL to DOX group.

Taken together, our results indicate that DIL treatment can reverse the resistance of breast cancer cells to the therapeutic effects of DOX and can protect against DOX-induced cardiotoxicity in rats.

• Cardiotoxicity
• Diltiazem
• Doxorubicin
• MCF-7 cells
• MDR

• MRI contrast
• breast cancer
• doxorubicin
• gene delivery
• hyaluronic acid
• multidrug resistance
• redox

In clinical practice, many patients become multidrug resistant during chemotherapy, resulting in reduced or no healing effect. Therefore, the present study focused on bufalin, which is extracted from a traditional Chinese medicine named Chan Su (Venenum bufonis). We assessed the effect of bufalin in reversing K562/A02 cell drug resistance and inducing apoptosis, and explored the possible mechanism by which bufalin induces K562/A02 cell apoptosis.

We used flow cytometry to evaluate intracellular ADM concentration, and RT-PCR and Western blot analysis were used to assess the effect of nuclear factor erythroid-2-related factor 2 (Nrf2) bufalin-related resistance gene expression. We used MTT and flow cytometry to detect apoptosis, and RT-PCR and Western blot were used to detect endoplasmic reticulum stress and apoptosis gene action.

We found that bufalin can increase the concentration of Adriamycin (ADM) in K562/A02 cells by inhibiting the expression of Nrf2 and related drug resistance factors. The results showed that bufalin induced apoptosis of K562/A02 cells by the IRE1α/TRAF2/JNK/caspase-12 pathway.

These results suggest bufalin can reverse drug resistance in K562/A02 cells and that it induces apoptosis of K562/A02 cells by the IRE1α/TRAF2/JNK/caspase-12 pathway.

• Cancer cell targeting
• Drug release stimulus
• Nanocarrier functionalization
• Smart drug delivery
• Smart nanocarrier
• Toxicity of nanocarrier

• ABCB1
• Doxorubicin
• HCC
• HDAC2
• c-Fos

Drug efflux induced by multidrug resistance (MDR) overexpression, as well as secondary drug resistance caused by subtoxic drug microenvironments as a result of inefficient drug release of nanoscopic drug carriers in tumor cells, are major bottlenecks for chemotherapy.

• multiple myeloma
• nanoparticles
• passive targeting
• targeted targeting
• triggered targeting

• active targeting
• endolysosomal escape
• enzyme and redox sensitive
• mesoporous silica nanoparticles
• multidrug resistance
• multilevel drug release

Multiple myeloma (MM) remains to be an incurable disease. The purpose of this study was to evaluate the effect of ABCG2 monoclonal antibody (McAb) combined with paclitaxel (PTX) conjugated with Fe₃O₄ nanoparticles (NPs) on MM progressed from cancer stem cells (CSCs)in non-obese-diabetic/severe-combined-immunodeficiency (NOD/SCID) mouse model. Mice were injected with MM CSCs as marked by CD138⁻CD34⁻ phenotypes through tail veins. The developed MM mice were examined by micro-computer tomography scanning, ultrasonography and enzyme-linked immunosorbent analysis. These mice were then intravenously treated with different combinations of NPs, PTX, McAb, PTX-NPs and melphalan/prednisone once a week for four weeks. The injected mice developed characteristic MM-associated syndromes, including lytic bone lesions, renal damages and proteinuria. All the treated mice showed decrease in bone lesions, renal damages and anemia but increase in apoptosis compared with the mice treated with NPs only. In particular, the treatment with ABCG2 McAb plus PTX-NPs induced the strongest therapeutic response and had an efficacy even better than that of melphalan/prednisone, a conventional regimen for MM patients. These data suggest that PTX-NPs with ABCG2 McAb can be developed into potential treatment regimens for patients with relapsed/refractory MM.

• ATP-binding cassette sub-family G member 2
• cancer stem cells
• multiple myeloma
• nanoparticles
• paclitaxel

• Combination therapy
• Liposome
• Lonidamine
• Multidrug resistance
• Paclitaxel

• 3-methyladenine
• apoptosis
• autophagy
• cisplatin
• osteosarcoma

CLN3 is a recently identified anti-apoptotic gene, which has been demonstrated to be highly expressed in a diverse range of cancer cell lines, including ovarian cancer. In the present study, RNA interference, mediated by a lentivirus expressing CLN3 short hairpin RNA (shRNA) was utilized to knockdown the expression of CLN3 in the A2780 human ovarian cancer cell line, and its cisplatin-resistant and carboplatin-resistant sublines, A2780/DDP and A2780/CBP cells. It was revealed that the mRNA and protein expression levels of CLN3 were significantly reduced in the CLN3-specific shRNA-transduced cells, compared with the untransduced and control shRNA-transduced cells. In addition, specific knockdown of CLN3 in these cells inhibited cell proliferation and led to cell cycle arrest at the G0/G1 phase, with eventual apoptosis. CLN3 knockdown caused increases in the levels of Bax, FAX, cleaved-caspase 3, cleaved-caspase 8 and cleaved-RARP, but decreased the level of Bcl-2. Finally, it was observed that CLN3 depletion markedly reduced the half maximum inhibitory concentration in the A2780/DDP and A2780/CBP cells. Taken together, these data suggested that CLN3 is involved in tumorigenesis and drug resistance in ovarian cancer, and may serve as a promising therapeutic target for its treatment.

• MRI
• SPIO
• paclitaxel
• superparamagnetic iron oxide

• antitumor agents
• cyclooxygenase inhibitors
• drug design
• platinum
• prodrugs

• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Combined Modality Therapy
• Drug Resistance, Neoplasm
• Hepatectomy
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/etiology
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Liver Transplantation
• MicroRNAs/analysis
• MicroRNAs/genetics
• Molecular Targeted Therapy
• Neoplasm Staging
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/therapeutic use
• Prognosis
• Sorafenib

• Antineoplastic Agents/chemistry
• Doxorubicin/chemistry
• Drug Delivery Systems
• Drug Stability
• Ferric Compounds/chemistry
• Liposomes/chemistry
• Magnetic Fields
• Micelles
• Models, Molecular
• Molecular Structure

Triple negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets, such as hormone receptors or human epidermal growth factor receptor type 2 (HER2); therefore, prognosis is poor. Bortezomib, a proteasome inhibitor, may exert efficacy in TNBC through its multiple cellular effects. Here, we tested the efficacy of bortezomib and examined the drug mechanism in breast cancer cells.

Five breast cancer cell lines: TNBC HCC-1937, MDA-MB-231, and MDA-MB-468; HER2-overexpressing MDA-MB-453; and estrogen receptor positive MCF-7 were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western Blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interfering RNA (siRNA). In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Immunohistochemical study was performed on tumor tissues from patients with TNBC.

Bortezomib induced significant apoptosis, which was independent of its proteasome inhibition, in the three TNBC cell lines, but not in MDA-MB-453 or MCF-7 cells. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of bortezomib. We showed that bortezomib inhibited CIP2A in association with p-Akt downregulation in a dose- and time-dependent manner in all sensitive TNBC cells, whereas no alterations in CIP2A expression and p-Akt were noted in bortezomib-resistant cells. Overexpression of CIP2A upregulated p-Akt and protected MDA-MB-231 and MDA-MB-468 cells from bortezomib-induced apoptosis, whereas silencing CIP2A by siRNA overcame the resistance to bortezomib-induced apoptosis in MCF-7 cells. In addition, bortezomib downregulated CIP2A mRNA but did not affect the degradation of CIP2A protein. Furthermore, bortezomib exerted in vivo antitumor activity in HCC-1937 xenografted tumors, but not in MCF-7 tumors. Bortezomib downregulated CIP2A expression in the HCC-1937 tumors but not in the MCF-7 tumors. Importantly, CIP2A expression is readily detectable in tumor samples from TNBC patients.

CIP2A is a major determinant mediating bortezomib-induced apoptosis in TNBC cells. CIP2A may thus be a potential therapeutic target in TNBC.

Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion.

• ABC transporter
• MDR
• MRP1
• P-gp
• review
• secondary metabolites