International Journal of Molecular Sciences

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12 pages, 8669 KiB

Open AccessArticle

Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia

by Keli Lima, Maria Fernanda Lopes Carvalho, Diego Antonio Pereira-Martins, Frederico Lisboa Nogueira, Lívia Bassani Lins de Miranda, Mariane Cristina do Nascimento, Rita de Cássia Cavaglieri, Jan Jacob Schuringa, João Agostinho Machado-Neto and Eduardo Magalhães Rego

Int. J. Mol. Sci. 2023, 24(23), 16899; https://doi.org/10.3390/ijms242316899 - 29 Nov 2023

Viewed by 1830

Abstract

Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P₂, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In [...] Read more.

Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P₂, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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15 pages, 539 KiB

Open AccessArticle

Characterization of Potential Melanoma Predisposition Genes in High-Risk Brazilian Patients

by Bianca Costa Soares de Sá, Luciana Facure Moredo, Giovana Tardin Torrezan, Felipe Fidalgo, Érica Sara Souza de Araújo, Maria Nirvana Formiga, João Pereira Duprat and Dirce Maria Carraro

Int. J. Mol. Sci. 2023, 24(21), 15830; https://doi.org/10.3390/ijms242115830 - 31 Oct 2023

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Abstract

Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4, risk variants in low- to moderate-penetrance genes (MC1R and MITF), and possibly due to variants in emerging genes, [...] Read more.

Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4, risk variants in low- to moderate-penetrance genes (MC1R and MITF), and possibly due to variants in emerging genes, such as ACD, TERF2IP, and TERT. We aimed to identify germline variants in high- and low- to moderate-penetrance melanoma risk genes in Brazilian patients with clinical criteria for familial melanoma syndrome. We selected patients with three or more melanomas or melanoma patients from families with three tumors (melanoma and pancreatic cancer) in first- or second-degree relatives. Genetic testing was performed with a nine-gene panel (ACD, BAP1, CDK4, CDKN2A, POT1, TERT, TERF2IP, MC1R, and MITF). In 36 patients, we identified 2 (5.6%) with germline pathogenic variants in CDKN2A and BAP1 and 4 (11.1%) with variants of uncertain significance in the high-penetrance genes. MC1R variants were found in 86.5%, and both red hair color variants and unknown risk variants were enriched in patients compared to a control group. The low frequency of germline pathogenic variants in the high-penetrance genes and the high prevalence of MC1R variants found in our cohort show the importance of the MC1R genotype in determining the risk of melanoma in the Brazilian melanoma-prone families. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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11 pages, 2380 KiB

Open AccessArticle

The Clinical and Molecular Profile of Lung Cancer Patients Harboring the TP53 R337H Germline Variant in a Brazilian Cancer Center: The Possible Mechanism of Carcinogenesis

by Carlos D. H. Lopes, Fernanda F. Antonacio, Priscila M. G. Moraes, Paula F. Asprino, Pedro A. F. Galante, Denis L. Jardim, Mariana P. de Macedo, Renata L. Sandoval, Artur Katz, Gilberto de Castro, Jr. and Maria Isabel Achatz

Int. J. Mol. Sci. 2023, 24(20), 15035; https://doi.org/10.3390/ijms242015035 - 10 Oct 2023

Cited by 3 | Viewed by 1566

Abstract

In southern and southeastern Brazil, the TP53 founder variant c.1010G>A (R337H) has been previously documented with a prevalence of 0.3% within the general population and linked to a heightened incidence of lung adenocarcinomas (LUADs). In the present investigation, we cover clinical and molecular [...] Read more.

In southern and southeastern Brazil, the TP53 founder variant c.1010G>A (R337H) has been previously documented with a prevalence of 0.3% within the general population and linked to a heightened incidence of lung adenocarcinomas (LUADs). In the present investigation, we cover clinical and molecular characterizations of lung cancer patients from the Brazilian Li-Fraumeni Syndrome Study (BLISS) database. Among the 175 diagnosed malignant neoplasms, 28 (16%) were classified as LUADs, predominantly occurring in females (68%), aged above 50 years, and never-smokers (78.6%). Significantly, LUADs manifested as the initial clinical presentation of Li-Fraumeni Syndrome in 78.6% of cases. Molecular profiling was available for 20 patients, with 14 (70%) revealing EGFR family alterations. In total, 23 alterations in cancer driver genes were identified, comprising 7 actionable mutations and 4 linked to resistance against systemic treatments. In conclusion, the carriers of TP53 R337H demonstrate a predisposition to LUAD development. Furthermore, our results indicate that environmental pollution potentially impacts the carcinogenesis of lung tumors in the carriers of TP53 R337H. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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16 pages, 3296 KiB

Open AccessArticle

Aspirin Affects MDA-MB-231 Vesicle Production and Their Capacity to Induce Fibroblasts towards a Pro-Invasive State

by Rafaela de Assiz Louback, Karina Martins-Cardoso, Luzineide W. Tinoco, Federica Collino, Ana Paula D. N. de Barros, Anneliese Fortuna-Costa, Robson Q. Monteiro, Maria Isabel Doria Rossi and Rafael Soares Lindoso

Int. J. Mol. Sci. 2023, 24(15), 12020; https://doi.org/10.3390/ijms241512020 - 27 Jul 2023

Cited by 1 | Viewed by 1661

Abstract

Long-term administration of aspirin (ASA, acetylsalicylic acid) in oncogenic patients has been related to a reduction in cancer risk incidence, but its precise mechanism of action is unclear. The activation of cancer-associated fibroblasts (CAFs) is a key element in tumor progression and can [...] Read more.

Long-term administration of aspirin (ASA, acetylsalicylic acid) in oncogenic patients has been related to a reduction in cancer risk incidence, but its precise mechanism of action is unclear. The activation of cancer-associated fibroblasts (CAFs) is a key element in tumor progression and can be triggered by cancer-derived extracellular vesicles (EVs). Targeting the communication between cancer cells and the surrounding tumor microenvironment (TME) may control cancer progression. Our aim was to investigate the effect of ASA on breast cancer cells, focusing on EV secretion and their effect on the biological properties of CAFs. As a result, ASA was shown to reduce the amount and alter the size distribution of EVs produced by MDA-MB-231 tumor cells. Fibroblasts stimulated with EVs derived from MDA-MB-231 treated with ASA (EV-ASA) showed a lower expression of alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP2) but not fibroblast activation protein (FAP) in respect to the ones stimulated with EVs from untreated breast cancer cells (EV-CTR). Furthermore, invasion assays using a three-dimensional (3D) fibroblast spheroid model showed reduced MDA-MB-231 invasion towards fibroblast spheroids pretreated with EV-ASA as compared to spheroids prepared with EV-CTR-stimulated fibroblasts. This suggests that ASA partially inhibits the ability of tumor EVs to stimulate CAFs to promote cancer invasion. In conclusion, ASA can interfere with tumor communication by reducing EV secretion by breast tumor cells as well as by interfering with their capacity to stimulate fibroblasts to become CAFs. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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12 pages, 1322 KiB

Open AccessArticle

Rectal Cancer Tissue Lipidome Differs According to Response to Neoadjuvant Therapy

by Salvador Sánchez-Vinces, Gustavo Henrique Bueno Duarte, Marcia Cristina Fernandes Messias, Caroline Fernanda Alves Gatinoni, Alex Ap. Rosini Silva, Pedro Henrique Godoy Sanches, Carlos Augusto Real Martinez, Andreia M. Porcari and Patricia de Oliveira Carvalho

Int. J. Mol. Sci. 2023, 24(14), 11479; https://doi.org/10.3390/ijms241411479 - 14 Jul 2023

Cited by 1 | Viewed by 1518

Abstract

Rectal cancer (RC) is a gastrointestinal cancer with a poor prognosis. While some studies have shown metabolic reprogramming to be linked to RC development, it is difficult to define biomolecules, like lipids, that help to understand cancer progression and response to therapy. The [...] Read more.

Rectal cancer (RC) is a gastrointestinal cancer with a poor prognosis. While some studies have shown metabolic reprogramming to be linked to RC development, it is difficult to define biomolecules, like lipids, that help to understand cancer progression and response to therapy. The present study investigated the relative lipid abundance in tumoral tissue associated with neoadjuvant therapy response using untargeted liquid chromatography–mass spectrometry lipidomics. Locally advanced rectal cancer (LARC) patients (n = 13), clinically staged as T3–4 were biopsied before neoadjuvant chemoradiotherapy (nCRT). Tissue samples collected before nCRT (staging) and afterwards (restaging) were analyzed to discover lipidomic differences in RC cancerous tissue from Responders (n = 7) and Non-responders (n = 6) to nCRT. The limma method was used to test differences between groups and to select relevant feature lipids from tissue samples. Simple glycosphingolipids and differences in some residues of glycerophospholipids were more abundant in the Non-responder group before and after nCRT. Oxidized glycerophospholipids were more abundant in samples of Non-responders, especially those collected after nCRT. This work identified potential lipids in tissue samples that take part in, or may explain, nCRT failure. These results could potentially provide a lipid-based explanation for nCRT response and also help in understanding the molecular basis of RC and nCRT effects on the tissue matrix. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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16 pages, 5579 KiB

Open AccessArticle

2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) Inhibits Proliferation and Invasion via Senescence Pathway Induction in Human BRAFi-Resistant Melanoma Cells

by Ylana Adami Franco, Manoel Oliveira de Moraes, Jr., Larissa A. C. Carvalho, Wolfgang Dohle, Renaira Oliveira da Silva, Isabella Harumi Yonehara Noma, Keli Lima, Barry V. L. Potter, João A. Machado-Neto and Silvya Stuchi Maria-Engler

Int. J. Mol. Sci. 2023, 24(14), 11314; https://doi.org/10.3390/ijms241411314 - 11 Jul 2023

Cited by 1 | Viewed by 1634

Abstract

The endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential as a therapeutic agent, acts by disrupting [...] Read more.

The endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential as a therapeutic agent, acts by disrupting microtubule polymerization, leading to cell cycle arrest and apoptosis in cancer cells and possesses much better pharmaceutical properties. This study investigated the antiproliferative and anti-invasive activities of STX140 in both SKMEL-28 naïve melanoma (SKMEL28-P) cells and resistant melanoma cells (SKMEL-28R). STX140 inhibited cell proliferation in the nanomolar range while having a less pronounced effect on human melanocytes. Additionally, STX140 induced cell cycle arrest in the G2/M phase and sub-G1, reduced migration, and clonogenic potential in monolayer models, and inhibited invasion in a 3D human skin model with melanoma cells. Furthermore, STX140 induced senescence features in melanoma and activated the senescence machinery by upregulating the expression of senescence genes and proteins related to senescence signaling. These findings suggest that STX140 may hold potential as a therapeutic agent for melanoma treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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16 pages, 3087 KiB

Open AccessArticle

Cathepsin B Is Not an Intrinsic Factor Related to Asparaginase Resistance of the Acute Lymphoblastic Leukemia REH Cell Line

by Iris Munhoz Costa, Brian Effer, Tales Alexandre Costa-Silva, Chen Chen, Michael F. Ciccone, Adalberto Pessoa, Camila O. dos Santos and Gisele Monteiro

Int. J. Mol. Sci. 2023, 24(13), 11215; https://doi.org/10.3390/ijms241311215 - 7 Jul 2023

Cited by 1 | Viewed by 1553

Abstract

L-Asparaginase (ASNase) is a biopharmaceutical used as an essential drug in the treatment of acute lymphoblastic leukemia (ALL). Yet, some cases of ALL are naturally resistant to ASNase treatment, which results in poor prognosis. The REH ALL cell line, used as a model [...] Read more.

L-Asparaginase (ASNase) is a biopharmaceutical used as an essential drug in the treatment of acute lymphoblastic leukemia (ALL). Yet, some cases of ALL are naturally resistant to ASNase treatment, which results in poor prognosis. The REH ALL cell line, used as a model for studying the most common subtype of ALL, is considered resistant to treatment with ASNase. Cathepsin B (CTSB) is one of the proteases involved in the regulation of in vivo ASNase serum half-life and it has also been associated with the progression and resistance to treatment of several solid tumors. Previous works have shown that, in vitro, ASNase is degraded when incubated with REH cell lysate, which is prevented by a specific CTSB inhibitor, suggesting a function of this protease in the ASNase resistance of REH cells. In this work, we utilized a combination of CRISPR/Cas9 gene targeting and enzymatic measurements to investigate the relevance of CTSB on ASNase treatment resistance in the ALL model cell line. We found that deletion of CTSB in REH ALL cells did not confer ASNase treatment sensitivity, thus suggesting that intrinsic expression of CTSB is not a mechanism that drives the resistant nature of these ALL cells to enzymes used as the first-line treatment against leukemia. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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27 pages, 5292 KiB

Open AccessArticle

Impairment of SK-MEL-28 Development—A Human Melanoma Cell Line—By the Crataeva tapia Bark Lectin and Its Sequence-Derived Peptides

by Kathleen Chwen Ming Lie, Camila Ramalho Bonturi, Bruno Ramos Salu, Juliana Rodrigues de Oliveira, Márcia Bonini Galo, Patrícia Maria Guedes Paiva, Maria Tereza dos Santos Correia and Maria Luiza Vilela Oliva

Int. J. Mol. Sci. 2023, 24(13), 10617; https://doi.org/10.3390/ijms241310617 - 25 Jun 2023

Cited by 4 | Viewed by 2012

Abstract

Melanoma is difficult to treat with chemotherapy, prompting the need for new treatments. Protease inhibitors have emerged as promising candidates as tumor cell proteases promote metastasis. Researchers have developed a chimeric form of the Bauhinia bauhinioides kallikrein inhibitor, rBbKIm, which has shown negative [...] Read more.

Melanoma is difficult to treat with chemotherapy, prompting the need for new treatments. Protease inhibitors have emerged as promising candidates as tumor cell proteases promote metastasis. Researchers have developed a chimeric form of the Bauhinia bauhinioides kallikrein inhibitor, rBbKIm, which has shown negative effects on prostate tumor cell lines DU145 and PC3. Crataeva tapia bark lectin, CrataBL, targets sulfated oligosaccharides in glycosylated proteins and has also demonstrated deleterious effects on prostate and glioblastoma tumor cells. However, neither rBbKIm nor its derived peptides affected the viability of SK-MEL-28, a melanoma cell line, while CrataBL decreased viability by over 60%. Two peptides, Pep. 26 (Ac-Q-N-S-S-L-K-V-V-P-L-NH2) and Pep. 27 (Ac-L-P-V-V-K-L-S-S-N-Q-NH2), were also tested. Pep. 27 suppressed cell migration and induced apoptosis when combined with vemurafenib, while Pep. 26 inhibited cell migration and reduced nitric oxide and the number of viable cells. Vemurafenib, a chemotherapy drug used to treat melanoma, was found to decrease the release of interleukin 8 and PDGF-AB/BB cytokines and potentiated the effects of proteins and peptides in reducing these cytokines. These findings suggest that protease inhibitors may be effective in blocking melanoma cells and highlight the potential of CrataBL and its derived peptides. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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22 pages, 2903 KiB

Open AccessArticle

Analysis of the Mutational Landscape of Osteosarcomas Identifies Genes Related to Metastasis and Prognosis and Disrupted Biological Pathways of Immune Response and Bone Development

by Sara Ferreira Pires, Juliana Sobral de Barros, Silvia Souza da Costa, Gabriel Bandeira do Carmo, Marília de Oliveira Scliar, André van Helvoort Lengert, Érica Boldrini, Sandra Regini Morini da Silva, Daniel Onofre Vidal, Mariana Maschietto and Ana Cristina Victorino Krepischi

Int. J. Mol. Sci. 2023, 24(13), 10463; https://doi.org/10.3390/ijms241310463 - 21 Jun 2023

Cited by 3 | Viewed by 2184

Abstract

Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian [...] Read more.

Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian patients, and identified 445 potentially deleterious SNVs/indels and 1176 copy number alterations (CNAs). TP53 was the most recurrently mutated gene, with an overall rate of ~60%, considering SNVs/indels and CNAs. The most frequent CNAs (~60%) were gains at 1q21.2q21.3, 6p21.1, and 8q13.3q24.22, and losses at 10q26 and 13q14.3q21.1. Seven cases presented CNA patterns reminiscent of complex events (chromothripsis and chromoanasynthesis). Putative RB1 and TP53 germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. PTPRQ, KNL1, ZFHX4, and DMD alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. TNFRSF11B, involved in skeletal system development and maintenance, emerged as a candidate for osteosarcomagenesis due to its biological function and a high frequency of copy number gains. A protein–protein network enrichment highlighted biological pathways involved in immunity and bone development. Our findings reinforced the high genomic OS instability and heterogeneity, and led to the identification of novel disrupted genes deserving further evaluation as biomarkers due to their association with poor outcomes. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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21 pages, 3811 KiB

Open AccessArticle

Molecular BCR::ABL1 Quantification and ABL1 Mutation Detection as Essential Tools for the Clinical Management of Chronic Myeloid Leukemia Patients: Results from a Brazilian Single-Center Study

by Anelis Maria Marin, Denise Kusma Wosniaki, Heloisa Bruna Soligo Sanchuki, Eduardo Cilião Munhoz, Jeanine Marie Nardin, Gabriela Silva Soares, Dhienifer Caroline Espinace, João Samuel de Holanda Farias, Bruna Veroneze, Luiz Felipe Becker, Guilherme Lima Costa, Olair Carlos Beltrame, Jaqueline Carvalho de Oliveira, Geison Cambri, Dalila Luciola Zanette and Mateus Nóbrega Aoki

Int. J. Mol. Sci. 2023, 24(12), 10118; https://doi.org/10.3390/ijms241210118 - 14 Jun 2023

Cited by 4 | Viewed by 2820

Abstract

Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. [...] Read more.

Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. The molecular detection of the BCR::ABL1 transcription is a required factor for CML diagnosis, and its molecular quantification is essential for assessing treatment options and clinical approaches. In the CML molecular context, point mutations on the ABL1 gene are also a challenge for clinical guidelines because several mutations are responsible for tyrosine kinase inhibitor resistance, indicating that a change may be necessary in the treatment protocol. So far, the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) have presented international guidelines on CML molecular approaches, especially those related to BCR::ABL1 expression. In this study, we show almost three years’ worth of data regarding the clinical treatment of CML patients at the Erasto Gaertner Hospital, Curitiba, Brazil. These data primarily comprise 155 patients and 532 clinical samples. BCR::ABL1 quantification by a duplex-one-step RT-qPCR and ABL1 mutations detection were conducted. Furthermore, digital PCR for both BCR::ABL1 expression and ABL1 mutations were conducted in a sub-cohort. This manuscript describes and discusses the clinical importance and relevance of molecular biology testing in Brazilian CML patients, demonstrating its cost-effectiveness. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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15 pages, 2268 KiB

Open AccessArticle

Glyphosate and Aminomethylphosphonic Acid (AMPA) Modulate Glutathione S-Transferase in Non-Tumorigenic Prostate Cells

by Dayanne Silva Borges, Lara Vecchi, Deysse Carla Tolentino Barros, Vinícius Marques Arruda, Helen Soares Valença Ferreira, Matheus Fernandes da Silva, Joyce Ferreira da Costa Guerra, Raoni Pais Siqueira and Thaise Gonçalves Araújo

Int. J. Mol. Sci. 2023, 24(7), 6323; https://doi.org/10.3390/ijms24076323 - 28 Mar 2023

Viewed by 1822

Abstract

Glyphosate (GLY) was developed in the early 1970s and has become the most used broad-spectrum herbicide in the world so far. Its main metabolite is aminomethylphosphonic acid (AMPA), and the accumulation of GLY and its derivative compounds raises some concerns regarding possible health [...] Read more.

Glyphosate (GLY) was developed in the early 1970s and has become the most used broad-spectrum herbicide in the world so far. Its main metabolite is aminomethylphosphonic acid (AMPA), and the accumulation of GLY and its derivative compounds raises some concerns regarding possible health outcomes. In this study, we aimed to evaluate the effects of GLY and AMPA on prostate cell lines by evaluating cell viability, proliferation, gene and protein expression, and cellular pathways involved in the response to oxidative stress. Our results indicated that GLY and AMPA reduced the cell viability of tumorigenic and non-tumorigenic prostate cell lines only at higher concentrations (10 mM GLY and 20 mM AMPA). In contrast, both compounds increased the clonogenicity of non-tumorigenic PNT2 cells, mainly at concentrations below the IC₅₀ (5 mM GLY and 10 mM AMPA). Moreover, treatment of non-tumorigenic cells with low concentrations of GLY or AMPA for 48 h increased GSTM3 expression at both mRNA and protein levels. In contrast, the treatments decrease the GST activity and induced an increase in oxidative stress, mainly at lower concentrations. Therefore, both compounds can cause cellular damage even at lower concentrations in non-tumorigenic PNT2 cells, mainly affecting cell proliferation and oxidative stress. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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Review

Jump to: Research

18 pages, 1262 KiB

Open AccessReview

Molecular Profile of Intrahepatic Cholangiocarcinoma

by Wellington Andraus, Francisco Tustumi, José Donizeti de Meira Junior, Rafael Soares Nunes Pinheiro, Daniel Reis Waisberg, Liliana Ducatti Lopes, Rubens Macedo Arantes, Vinicius Rocha Santos, Rodrigo Bronze de Martino and Luiz Augusto Carneiro D’Albuquerque

Int. J. Mol. Sci. 2024, 25(1), 461; https://doi.org/10.3390/ijms25010461 - 29 Dec 2023

Cited by 5 | Viewed by 2253

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of [...] Read more.

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of ICC tumors sheds light on the disease’s underlying biology and offers a foundation for more personalized treatment strategies. This is a narrative review of the prognostic and therapeutic role of the molecular profile of ICC. Knowing the molecular profile of tumors helps determine prognosis and support certain target therapies. The molecular panel in ICC helps to select patients for specific therapies, predict treatment responses, and monitor treatment responses. Precision medicine in ICC can promote improvement in prognosis and reduce unnecessary toxicity and might have a significant role in the management of ICC in the following years. The main mutations in ICC are in tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), and AT-rich interactive domain-containing protein 1A (ARID1A). The rate of mutations varies significantly for each population. Targeting TP53 and KRAS is challenging due to the natural characteristics of these genes. Different stages of clinical studies have shown encouraging results with inhibitors of mutated IDH1 and target therapy for ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions are an important target in patients with ICC. Immune checkpoint blockade can be applied to a small percentage of ICC patients. Molecular profiling in ICC represents a groundbreaking approach to understanding and managing this complex liver cancer. As our comprehension of ICC’s molecular intricacies continues to expand, so does the potential for offering patients more precise and effective treatments. The integration of molecular profiling into clinical practice signifies the dawn of a new era in ICC care, emphasizing personalized medicine in the ongoing battle against this malignancy. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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29 pages, 3891 KiB

Open AccessReview

A Strategy Utilizing Protein–Protein Interaction Hubs for the Treatment of Cancer Diseases

by Nicolas Carels, Domenico Sgariglia, Marcos Guilherme Vieira Junior, Carlyle Ribeiro Lima, Flávia Raquel Gonçalves Carneiro, Gilberto Ferreira da Silva, Fabricio Alves Barbosa da Silva, Rafaela Scardini, Jack Adam Tuszynski, Cecilia Vianna de Andrade, Ana Carolina Monteiro, Marcel Guimarães Martins, Talita Goulart da Silva, Helen Ferraz, Priscilla Vanessa Finotelli, Tiago Albertini Balbino and José Carlos Pinto

Int. J. Mol. Sci. 2023, 24(22), 16098; https://doi.org/10.3390/ijms242216098 - 8 Nov 2023

Cited by 2 | Viewed by 2430

Abstract

We describe a strategy for the development of a rational approach of neoplastic disease therapy based on the demonstration that scale-free networks are susceptible to specific attacks directed against its connective hubs. This strategy involves the (i) selection of up-regulated hubs of connectivity [...] Read more.

We describe a strategy for the development of a rational approach of neoplastic disease therapy based on the demonstration that scale-free networks are susceptible to specific attacks directed against its connective hubs. This strategy involves the (i) selection of up-regulated hubs of connectivity in the tumors interactome, (ii) drug repurposing of these hubs, (iii) RNA silencing of non-druggable hubs, (iv) in vitro hub validation, (v) tumor-on-a-chip, (vi) in vivo validation, and (vii) clinical trial. Hubs are protein targets that are assessed as targets for rational therapy of cancer in the context of personalized oncology. We confirmed the existence of a negative correlation between malignant cell aggressivity and the target number needed for specific drugs or RNA interference (RNAi) to maximize the benefit to the patient’s overall survival. Interestingly, we found that some additional proteins not generally targeted by drug treatments might justify the addition of inhibitors designed against them in order to improve therapeutic outcomes. However, many proteins are not druggable, or the available pharmacopeia for these targets is limited, which justifies a therapy based on encapsulated RNAi. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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33 pages, 2916 KiB

Open AccessReview

Deciphering the Functional Status of Breast Cancers through the Analysis of Their Extracellular Vesicles

by Alexis Germán Murillo Carrasco, Andreia Hanada Otake, Janaina Macedo-da-Silva, Veronica Feijoli Santiago, Giuseppe Palmisano, Luciana Nogueira de Sousa Andrade and Roger Chammas

Int. J. Mol. Sci. 2023, 24(16), 13022; https://doi.org/10.3390/ijms241613022 - 21 Aug 2023

Cited by 2 | Viewed by 2600

Abstract

Breast cancer (BC) accounts for the highest incidence of tumor-related mortality among women worldwide, justifying the growing search for molecular tools for the early diagnosis and follow-up of BC patients under treatment. Circulating extracellular vesicles (EVs) are membranous nanocompartments produced by all human [...] Read more.

Breast cancer (BC) accounts for the highest incidence of tumor-related mortality among women worldwide, justifying the growing search for molecular tools for the early diagnosis and follow-up of BC patients under treatment. Circulating extracellular vesicles (EVs) are membranous nanocompartments produced by all human cells, including tumor cells. Since minimally invasive methods collect EVs, which represent reservoirs of signals for cell communication, these particles have attracted the interest of many researchers aiming to improve BC screening and treatment. Here, we analyzed the cargoes of BC-derived EVs, both proteins and nucleic acids, which yielded a comprehensive list of potential markers divided into four distinct categories, namely, (i) modulation of aggressiveness and growth; (ii) preparation of the pre-metastatic niche; (iii) epithelial-to-mesenchymal transition; and (iv) drug resistance phenotype, further classified according to their specificity and sensitivity as vesicular BC biomarkers. We discuss the therapeutic potential of and barriers to the clinical implementation of EV-based tests, including the heterogeneity of EVs and the available technologies for analyzing their content, to present a consistent, reproducible, and affordable set of markers for further evaluation. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)

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