Articles
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Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance
Cancer Drug Resist 2023;6:103-15. DOI: 10.20517/cdr.2022.96AbstractAim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast ... MOREAim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel.Methods: The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months.Results: The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells(P < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 <MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC50 value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (P < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells.Conclusion: Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression. LESS Full articleOriginal Article|Published on: 7 Feb 2023 -
Nano-TRAIL: a promising path to cancer therapy
Cancer Drug Resist 2023;6:78-102. DOI: 10.20517/cdr.2022.82AbstractTumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers ... MORETumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers apoptosis by binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors. Apoptosis occurs through either the extrinsic or intrinsic pathway. The administration of recombinant human TRAIL (rhTRAIL) or TRAIL-receptor (TRAIL-R) agonists promotes apoptosis preferentially in cancerous cells over normal cells in vitro; this phenomenon has also been observed in clinical studies. The limited efficacy of rhTRAIL in clinical trials could be attributed to drug resistance, short half-life, targeted delivery issues, and off-target toxicities. Nanoparticles are excellent drug and gene delivery systems characterized by improved permeability and retention, increased stability and biocompatibility, and precision targeting. In this review, we discuss resistance mechanisms to TRAIL and methods to overcome TRAIL resistance by using nanoparticle-based formulations developed for the delivery of TRAIL peptides, TRAIL-R agonists, and TRAIL genes to cancer cells. We also discuss combinatorial approaches of chemotherapeutic drugs with TRAIL. These studies demonstrate TRAIL’s potential as an anticancer agent. LESS Full articleReview|Published on: 1 Feb 2023 -
Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities
Cancer Drug Resist 2023;6:59-77. DOI: 10.20517/cdr.2022.90AbstractAim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, ... MOREAim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties.Methods: 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromid (MTT) assay], effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative.Results: Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo.Conclusion: The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, andanti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates. LESS Full articleOriginal Article|Published on: 1 Feb 2023 -
The change of paradigm in the treatment of HER2-positive breast cancer with the development of new generation antibody-drug conjugates
Cancer Drug Resist 2023;6:45-58. DOI: 10.20517/cdr.2022.52AbstractHER2-positive breast cancer is an aggressive disease. As a result of the development of specific ... MOREHER2-positive breast cancer is an aggressive disease. As a result of the development of specific HER2-targeted therapies, such as trastuzumab, more than 20 years ago, the prognosis of these patients has improved. Metastatic HER2-positive breast cancer patients are achieving better survival rates upon treatment with anti-HER2 therapies than patients with HER2-negative disease. Double HER2 blockade with trastuzumab and pertuzumab combined with a taxane achieved an unprecedented survival of over 57 months in first-line patients. Trastuzumab emtansine, the first antibody-drug conjugate approved for patients in second-line treatment was a potent cytotoxic agent bound to trastuzumab and is currently a standard therapeutic strategy. Despite the progress in treatment development, most patients develop resistance and eventually relapse. Advances in the design of antibody-drug conjugates have led to the development of new generation drugs with enhanced properties, such as trastuzumab deruxtecan and trastuzumab duocarmazine, which are significantly changing the paradigm in the treatment of HER2-positive metastatic breast cancer. LESS Full articleOpinion|Published on: 12 Jan 2023 -
New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers
Cancer Drug Resist 2023;6:35-44. DOI: 10.20517/cdr.2022.73AbstractThe clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ... MOREThe clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers. LESS Full articleCommentary|Published on: 4 Jan 2023 -
Concomitant medications and circulating tumor cells: friends or foes?
Cancer Drug Resist 2023;6:30-4. DOI: 10.20517/cdr.2022.68AbstractThe use of concomitant medications by patients with cancer is observed almost globally; however, little ... MOREThe use of concomitant medications by patients with cancer is observed almost globally; however, little attention has been paid to this topic in the medical literature. Most clinical studies do not describe the type and duration of drugs used at the time of inclusion and during treatment or how these drugs may affect the experimental and/or standard therapy. Even less information has been published on the potential interaction between concomitant medications and tumor biomarkers. However, we do know that concomitant drugs can complicate cancer clinical trials and biomarker development, thus contributing to their interaction, leading to side effects, and resulting in suboptimal adherence to anticancer treatment. On the basis of these premises and moving from the study by Jurisova et al., which reported the effect of commonly used drugs on the prognosis of women with breast cancer and the detection of circulating tumor cells (CTCs), we comment on the role of CTCs as an emerging diagnostic and prognostic tool for breast cancer. We also report the known and hypothesized mechanisms of CTC interplay with other tumor and blood components, possibly modulated by widespread drugs, including over-the-counter compounds, and discuss the possible implications of commonly used concomitant medications on CTC detection and clearance. After considering all these points, it is conceivable that concomitant drugs are not necessarily a problem, but on the contrary, their virtuous mechanisms can be exploited to reduce tumor spread and enhance the effect of anticancer therapies. LESS Full articleCommentary|Published on: 4 Jan 2023
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Most Cited Papers In Last Two Years
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Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review
Cancer Drug Resist 2021;4:17-43. DOI: 10.20517/cdr.2020.79AbstractGlioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an ... MOREGlioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance. LESS Full articleReview|Published on: 19 Mar 2021 -
Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia
Cancer Drug Resist 2021;4:125-42. DOI: 10.20517/cdr.2020.95AbstractDespite the success of the combination of venetoclax with the hypomethylating agents (HMA) decitabine or ... MOREDespite the success of the combination of venetoclax with the hypomethylating agents (HMA) decitabine or azacitidine in inducing remission in older, previously untreated patients with acute myeloid leukemia (AML), resistance - primary or secondary - still constitutes a significant roadblock in the quest to prolong the duration of response. Here we review the proposed and proven mechanisms of resistance to venetoclax monotherapy, HMA monotherapy, and the doublet of venetoclax and HMA for the treatment of AML. We approach the mechanisms of resistance to HMAs and venetoclax in the light of the agents’ mechanisms of action. We briefly describe potential therapeutic strategies to circumvent resistance to this promising combination, including alternative scheduling or the addition of other agents to the HMA and venetoclax backbone. Understanding the mechanisms of action and evolving resistance in AML remains a priority in order to maximize the benefit from novel drugs and combinations, identify new therapeutic targets, define potential prognostic markers, and avoid treatment failure. LESS Full articleReview|Published on: 19 Mar 2021 -
Regulation of cancer stem cells in triple negative breast cancer
Cancer Drug Resist 2021;4:321-42. DOI: 10.20517/cdr.2020.106AbstractTriple Negative Breast Cancer (TNBC) is the most lethal subtype of breast cancer. Despite the ... MORETriple Negative Breast Cancer (TNBC) is the most lethal subtype of breast cancer. Despite the successes of emerging targeted therapies, relapse, recurrence, and therapy failure rates in TNBC significantly outpace other subtypes of breast cancer. Mounting evidence suggests accumulation of therapy resistant Cancer Stem Cell (CSC) populations within TNBCs contributes to poor clinical outcomes. These CSCs are enriched in TNBC compared to non-TNBC breast cancers. The mechanisms underlying CSC accumulation have been well-characterized and discussed in other reviews. In this review, we focus on TNBC-specific mechanisms that allow the expansion and activity of self-renewing CSCs. We highlight cellular signaling pathways and transcription factors, specifically enriched in TNBC over non-TNBC breast cancer, contributing to stemness. We also analyze publicly available single-cell RNA-seq data from basal breast cancer tumors to highlight the potential of emerging bioinformatic approaches in identifying novel drivers of stemness in TNBC and other cancers. LESS Full articleReview|Published on: 19 Jun 2021 -
The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors
Cancer Drug Resist 2021;4:784-804. DOI: 10.20517/cdr.2021.19AbstractThe ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are multidrug transporters that confer drug ... MOREThe ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are multidrug transporters that confer drug resistance to numerous anti-cancer therapeutics in cell culture. These findings initially created great excitement in the medical oncology community, as inhibitors of these transporters held the promise of overcoming clinical multidrug resistance in cancer patients. However, clinical trials of P-gp and ABCG2 inhibitors in combination with cancer chemotherapeutics have not been successful due, in part, to flawed clinical trial designs resulting from an incomplete molecular understanding of the multifactorial basis of multidrug resistance (MDR) in the cancers examined. The field was also stymied by the lack of high-resolution structural information for P-gp and ABCG2 for use in the rational structure-based drug design of inhibitors. Recent advances in structural biology have led to numerous structures of both ABCG2 and P-gp that elucidated more clearly the mechanism of transport and the polyspecific nature of their substrate and inhibitor binding sites. These data should prove useful helpful for developing even more potent and specific inhibitors of both transporters. As such, although possible pharmacokinetic interactions would need to be evaluated, these inhibitors may show greater effectiveness in overcoming ABC-dependent multidrug resistance in combination with chemotherapeutics in carefully selected subsets of cancers. Another perhaps even more compelling use of these inhibitors may be in reversibly inhibiting endogenously expressed P-gp and ABCG2, which serve a protective role at various blood-tissue barriers. Inhibition of these transporters at sanctuary sites such as the brain and gut could lead to increased penetration by chemotherapeutics used to treat brain cancers or other brain disorders and increased oral bioavailability of these agents, respectively. LESS Full articleReview|Published on: 4 Aug 2021
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