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Keywords = imatinib (Gleevec)

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20 pages, 1597 KiB  
Review
Oncogenic Fusions Harboring ETS Genes: Exploring Novel Targetable Opportunities in Prostate Cancer
by Federica De Cecco, Lidia Chellini, Veronica Riccioni and Maria Paola Paronetto
Cancers 2025, 17(10), 1657; https://doi.org/10.3390/cancers17101657 - 14 May 2025
Viewed by 588
Abstract
Chromosomal rearrangements are implicated in the pathogenesis of several human malignancies, but, concurrently, they also represent targetable opportunities, as exemplified by imatinib (Gleevec), which targets the BCR-ABL gene fusion in myeloid leukemia. In prostate cancer, several chromosomal rearrangements have been identified, most of [...] Read more.
Chromosomal rearrangements are implicated in the pathogenesis of several human malignancies, but, concurrently, they also represent targetable opportunities, as exemplified by imatinib (Gleevec), which targets the BCR-ABL gene fusion in myeloid leukemia. In prostate cancer, several chromosomal rearrangements have been identified, most of them involving ETS genes, which encode key transcription factors. In this review, we explore the discovery of 5′ partners that classify ETS gene fusions into distinct groups based on the prostate specificity and androgen responsiveness. Furthermore, we try to address the relationship between gene fusion status and patient outcomes and discuss the possibility of using prostate-specific targeting of ETS gene fusions in cancer detection, stratification, and treatment. Full article
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26 pages, 6313 KiB  
Article
Unraveling the Mechanisms of Sensitivity to Anti-FGF Therapies in Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Lacking Secondary KIT Mutations
by Sergei Boichuk, Pavel Dunaev, Vera Skripova, Aigul Galembikova, Firyuza Bikinieva, Elena Shagimardanova, Guzel Gazizova, Ruslan Deviatiiarov, Elena Valeeva, Ekaterina Mikheeva, Maria Vasilyeva, Pavel Kopnin, Vladimir Strelnikov and Ramziya Kiyamova
Cancers 2023, 15(22), 5354; https://doi.org/10.3390/cancers15225354 - 9 Nov 2023
Cited by 7 | Viewed by 2231
Abstract
We showed previously that inhibition of KIT signaling in GISTs activates FGFR-signaling pathway rendering cancer cells resistant to receptor tyrosine kinase inhibitor (RTKi) imatinib mesylate (IM) (Gleevec) despite of absence of secondary KIT mutations and thereby illustrating a rationale for the combined (e.g., [...] Read more.
We showed previously that inhibition of KIT signaling in GISTs activates FGFR-signaling pathway rendering cancer cells resistant to receptor tyrosine kinase inhibitor (RTKi) imatinib mesylate (IM) (Gleevec) despite of absence of secondary KIT mutations and thereby illustrating a rationale for the combined (e.g., KIT- and FGFR-targeted) therapies. We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398′s activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway). Full article
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8 pages, 550 KiB  
Case Report
Bullous Pemphigoid Occurring after Stopping Imatinib Therapy of CML: Is a Continuation of Post-Treatment Follow-Up Needed?
by Alexander Yakobson, Ala Eddin Neime, Omar Abu Saleh, Kayed Al Athamen and Walid Shalata
Clin. Pract. 2023, 13(5), 1082-1089; https://doi.org/10.3390/clinpract13050096 - 5 Sep 2023
Cited by 2 | Viewed by 1748
Abstract
Advancements and the use of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of Chronic Myeloid Leukemia (CML), achieving unprecedented success rates and expanding their applications to various neoplasms. However, the use of TKIs is not without its drawbacks. Skin, gastrointestinal, and central [...] Read more.
Advancements and the use of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of Chronic Myeloid Leukemia (CML), achieving unprecedented success rates and expanding their applications to various neoplasms. However, the use of TKIs is not without its drawbacks. Skin, gastrointestinal, and central nervous systems are particularly susceptible to adverse effects, including a higher incidence of autoimmune responses in treated individuals. In this report, we present a unique case of bullous pemphigoid, a rare autoimmune disease, which has not been previously associated with TKI therapy as an adverse effect, particularly appearing after discontinuing Imatinib® treatment. Full article
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11 pages, 2628 KiB  
Review
Recent Advances in the Synthesis of Piperazines: Focus on C–H Functionalization
by Carolina Durand and Michal Szostak
Organics 2021, 2(4), 337-347; https://doi.org/10.3390/org2040018 - 8 Oct 2021
Cited by 18 | Viewed by 10606
Abstract
Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural [...] Read more.
Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural diversity of piperazines is limited, with about 80% of piperazine-containing drugs containing substituents only at the nitrogen positions. Recently, major advances have been made in the C–H functionalization of the carbon atoms of the piperazine ring. Herein, we present an overview of the recent synthetic methods to afford functionalized piperazines with a focus on C–H functionalization. Full article
(This article belongs to the Special Issue Feature Papers in Organics)
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10 pages, 2470 KiB  
Article
Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles
by You-Zhe Lin, Yi-Chun Shen, Wan-Rong Wu, Wei-Jan Wang, Yuan-Liang Wang, Chen-Yuan Lin, Mien-Chie Hung and Shao-Chun Wang
Int. J. Mol. Sci. 2021, 22(13), 6938; https://doi.org/10.3390/ijms22136938 - 28 Jun 2021
Cited by 9 | Viewed by 3775
Abstract
A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as [...] Read more.
A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19. Full article
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17 pages, 3218 KiB  
Article
Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer
by Chiharu Sogawa, Takanori Eguchi, Yuri Namba, Yuka Okusha, Eriko Aoyama, Kazumi Ohyama and Kuniaki Okamoto
Cells 2021, 10(2), 344; https://doi.org/10.3390/cells10020344 - 6 Feb 2021
Cited by 25 | Viewed by 6395
Abstract
Researchers have developed several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids with increased properties of cancer stem cells (CSCs), also called cancer-initiating cells (CICs). Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anti-cancer drugs have [...] Read more.
Researchers have developed several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids with increased properties of cancer stem cells (CSCs), also called cancer-initiating cells (CICs). Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anti-cancer drugs have been reported using 2D culture systems, whereas 3D cultured tumoroids have many advantages for assessing drug sensitivity and resistance. Here, we aimed to investigate whether Cisplatin (a DNA crosslinker), Imatinib (a multiple tyrosine kinase inhibitor), and 5-Fluorouracil (5-FU: an antimetabolite) alter the tumoroid growth of metastatic colorectal cancer (mCRC). Gene expression signatures of highly metastatic aggregative CRC (LuM1 cells) vs. low-metastatic, non-aggregative CRC (Colon26 and NM11 cells) were analyzed using microarray. To establish a 3D culture-based multiplexing reporter assay system, LuM1 was stably transfected with the Mmp9 promoter-driven ZsGreen fluorescence reporter gene, which was designated as LuM1/m9 cells and cultured in NanoCulture Plate®, a gel-free 3D culture device. LuM1 cells highly expressed mRNA encoding ABCG2 (a drug resistance pump, i.e., CSC/CIC marker), other CSC/CIC markers (DLL1, EpCAM, podoplanin, STAT3/5), pluripotent stem cell markers (Sox4/7, N-myc, GATA3, Nanog), and metastatic markers (MMPs, Integrins, EGFR), compared to the other two cell types. Hoechst efflux stem cell-like side population was increased in LuM1 (7.8%) compared with Colon26 (2.9%), both of which were markedly reduced by verapamil treatment, an ABCG2 inhibitor. Smaller cell aggregates of LuM1 were more sensitive to Cisplatin (at 10 μM), whereas larger tumoroids with increased ABCG2 expression were insensitive. Notably, Cisplatin (2 μM) and Imatinib (10 μM) at low concentrations significantly promoted tumoroid formation (cell aggregation) and increased Mmp9 promoter activity in mCRC LuM1/m9, while not cytotoxic to them. On the other hand, 5-FU significantly inhibited tumoroid growth, although not completely. Thus, drug resistance in cancer with increased stem cell properties was modeled using the gel-free 3D cultured tumoroid system. The tumoroid culture is useful and easily accessible for the assessment of drug sensitivity and resistance. Full article
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15 pages, 5510 KiB  
Article
Imatinib Sets Pericyte Mosaic in the Retina
by Tamás Kovács-Öller, Elena Ivanova, Gergely Szarka, Ádám J. Tengölics, Béla Völgyi and Botir T. Sagdullaev
Int. J. Mol. Sci. 2020, 21(7), 2522; https://doi.org/10.3390/ijms21072522 - 5 Apr 2020
Cited by 7 | Viewed by 4110
Abstract
The nervous system demands an adequate oxygen and metabolite exchange, making pericytes (PCs), the only vasoactive cells on the capillaries, essential to neural function. Loss of PCs is a hallmark of multiple diseases, including diabetes, Alzheimer’s, amyotrophic lateral sclerosis (ALS) and Parkinson’s. Platelet-derived [...] Read more.
The nervous system demands an adequate oxygen and metabolite exchange, making pericytes (PCs), the only vasoactive cells on the capillaries, essential to neural function. Loss of PCs is a hallmark of multiple diseases, including diabetes, Alzheimer’s, amyotrophic lateral sclerosis (ALS) and Parkinson’s. Platelet-derived growth factor receptors (PDGFRs) have been shown to be critical to PC function and survival. However, how PDGFR-mediated PC activity affects vascular homeostasis is not fully understood. Here, we tested the hypothesis that imatinib, a chemotherapeutic agent and a potent PDGFR inhibitor, alters PC distribution and thus induces vascular atrophy. We performed a morphometric analysis of the vascular elements in sham control and imatinib-treated NG2-DsRed mice. Vascular morphology and the integrity of the blood–retina barrier (BRB) were evaluated using blood albumin labeling. We found that imatinib decreased the number of PCs and blood vessel (BV) coverage in all retinal vascular layers; this was accompanied by a shrinkage of BV diameters. Surprisingly, the total length of capillaries was not altered, suggesting a preferential effect of imatinib on PCs. Furthermore, blood–retina barrier disruption was not evident. In conclusion, our data suggest that imatinib could help in treating neurovascular diseases and serve as a model for PC loss, without BRB disruption. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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16 pages, 4236 KiB  
Article
HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells
by Shu-Huey Chen, Jyh-Ming Chow, Yao-Yu Hsieh, Chun-Yu Lin, Kai-Wen Hsu, Wen-Shyang Hsieh, Wei-Ming Chi, Beished M. Shabangu and Chia-Hwa Lee
Int. J. Mol. Sci. 2019, 20(9), 2271; https://doi.org/10.3390/ijms20092271 - 8 May 2019
Cited by 28 | Viewed by 6095
Abstract
Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%–20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated [...] Read more.
Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%–20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase and eventually to a blast crisis, limiting treatment options and resulting in a poor survival rate. Thus, we investigated whether histone deacetylase inhibitors (HDACis) could be used as a potential anticancer therapy for imatinib-resistant CML (IR-CML) patients. By applying a noninvasive apoptosis detection sensor (NIADS), we found that panobinostat significantly enhanced cell apoptosis in K562 cells. A further investigation showed that panobinostat induced apoptosis in both K562 and imatinib-resistant K562 (IR-K562) cells mainly via H3 and H4 histone acetylation, whereas panobinostat targeted cancer stem cells (CSCs) in IR-K562 cells. Using CRISPR/Cas9 genomic editing, we found that HDAC1 and HDAC2 knockout cells significantly induced cell apoptosis, indicating that the regulation of HDAC1 and HDAC2 is extremely important in maintaining K562 cell survival. All information in this study indicates that regulating HDAC activity provides therapeutic benefits against CML and IR-CML in the clinic. Full article
(This article belongs to the Special Issue Roles of HDACs and HDAC Inhibitors in Human Cancers)
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17 pages, 2484 KiB  
Article
Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model
by Ewa Maj, Beata Filip-Psurska, Marta Świtalska, Andrzej Kutner and Joanna Wietrzyk
Int. J. Mol. Sci. 2015, 16(11), 27191-27207; https://doi.org/10.3390/ijms161126016 - 13 Nov 2015
Cited by 24 | Viewed by 7141
Abstract
In previous papers, we presented data on studies on the anticancer activity of the vitamin D3 analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) [...] Read more.
In previous papers, we presented data on studies on the anticancer activity of the vitamin D3 analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins. Full article
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18 pages, 859 KiB  
Review
Historical Perspectives in the Development of Antiviral Agents Against Poxviruses
by Erik De Clercq
Viruses 2010, 2(6), 1322-1339; https://doi.org/10.3390/v2061322 - 14 Jun 2010
Cited by 36 | Viewed by 10238
Abstract
The poxvirus vaccinia virus (VV) served as the model virus for which the first antivirals, the thiosemicarbazones, were identified. This dates back to 1950; and, although there is at present no single antiviral drug specifically licensed for the chemotherapy or -prophylaxis of poxvirus [...] Read more.
The poxvirus vaccinia virus (VV) served as the model virus for which the first antivirals, the thiosemicarbazones, were identified. This dates back to 1950; and, although there is at present no single antiviral drug specifically licensed for the chemotherapy or -prophylaxis of poxvirus infections, numerous candidate compounds have been described over the past 50 years. These compounds include interferon and inducers thereof (i.e., polyacrylic acid), 5-substituted 2’-deoxyuridines (i.e., idoxuridine), IMP dehydrogenase inhibitors, S-adenosylhomocysteine hydrolase inhibitors, acyclic nucleoside phosphonates (such as cidofovir) and alkoxyalkyl prodrugs thereof (such as CMX001), viral egress inhibitors (such as tecovirimat), and cellular kinase inhibitors (such as imatinib). Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
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7 pages, 169 KiB  
Review
Tyrosine Kinase Inhibitors as Antiangiogenic Drugs in Multiple Myeloma
by Domenico Ribatti
Pharmaceuticals 2010, 3(4), 1225-1231; https://doi.org/10.3390/ph3041225 - 22 Apr 2010
Cited by 7 | Viewed by 10186
Abstract
Tyrosine kinase inhibitors are a new class of anticancer drugs, that are capable of directly interacting with the catalytic site of the target enzyme and thereby inhibiting catalysis. Therapeutically useful tyrosine kinase inhibitors are not specific for a single tyrosine kinase, but rather [...] Read more.
Tyrosine kinase inhibitors are a new class of anticancer drugs, that are capable of directly interacting with the catalytic site of the target enzyme and thereby inhibiting catalysis. Therapeutically useful tyrosine kinase inhibitors are not specific for a single tyrosine kinase, but rather they are selective against a limited number of tyrosine kinases. The success of imatinib-mesylate (Gleevec®) for the treatment of patients with chronic myeloid leukemia has opened a intensive search for new small molecular compounds able to target other protein tyrosine kinases involved in the malignant transformation. This review article is focused on the use of tyrosine kinase inhibitors as antiangiogenic molecules in the treatment of multiple myeloma. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors)
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