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Article ; Online: Therapeutic opportunities for PLK1 inhibitors: Spotlight on BRCA1-deficiency and triple negative breast cancers.

García, Iris Alejandra / Garro, Cintia / Fernandez, Elmer / Soria, Gastón

2020 Volume 821, Page(s) 111693

Abstract: Polo-Like Kinases (PLKs) are central players of mitotic progression in Eukaryotes. Given the intimate relationship between cell cycle progression and cancer development, PLKs in general and PLK1 in particular have been thoroughly studied as biomarkers ... ...

Abstract	Polo-Like Kinases (PLKs) are central players of mitotic progression in Eukaryotes. Given the intimate relationship between cell cycle progression and cancer development, PLKs in general and PLK1 in particular have been thoroughly studied as biomarkers and potential therapeutic targets in oncology. The oncogenic properties of PLK1 overexpression across different types of human cancers are attributed to its roles in promoting mitotic entry, centrosome maturation, spindle assembly and cytokinesis. While several academic labs and pharmaceutical companies were able to develop potent and selective inhibitors of PLK1 (PLK1i) for preclinical research, such compounds have reached only limited success in clinical trials despite their great pharmacokinetics. Even though this could be attributed to multiple causes, the housekeeping roles of PLK1 in both normal and cancer cells are most likely the main reason for clinical trials failure and withdraw due to toxicities issues. Therefore, great efforts are being invested to position PLK1i in the treatment of specific types of cancers with revised dosages schemes. In this mini review we focus on two potential niches for PLK1i that are supported by recent evidence: triple negative breast cancers (TNBCs) and BRCA1-deficient cancers. On the one hand, we recollect several lines of strong evidence indicating that TNBCs are among the cancers with highest PLK1 expression and sensitivity to PLK1i. These findings are encouraging because of the limited therapeutics options available for TNBC patients, which rely mainly on classic chemotherapy. On the other hand, we discuss recent evidence that unveils synthetic lethality induction by PLK1 inhibition in BRCA1-deficient cancers cells. This previously unforeseen therapeutic link between PLK1 and BRCA1 is promising because it defines novel therapeutic opportunities for PLK1i not only for breast cancer (i.e. TNBCs with BRCA1 deficiencies), but also for other types of cancers with BRCA1-deficiencies, such as pancreatic and prostate cancers.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; BRCA1 Protein/deficiency ; Cell Cycle Proteins/antagonists & inhibitors ; Humans ; Molecular Targeted Therapy ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Proto-Oncogene Proteins/antagonists & inhibitors ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology ; Polo-Like Kinase 1
Chemical Substances	Antineoplastic Agents ; BRCA1 Protein ; BRCA1 protein, human ; Cell Cycle Proteins ; Proto-Oncogene Proteins ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2020-02-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	206607-5
ISSN	1873-135X ; 1383-5718 ; 0027-5107 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
ISSN (online)	1873-135X
ISSN	1383-5718 ; 0027-5107 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
DOI	10.1016/j.mrfmmm.2020.111693
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Article: Topical Systems for the Controlled Release of Antineoplastic Drugs: Oxidized Alginate-Gelatin Hydrogel/Unilamellar Vesicles

Stagnoli, Soledad / Garro, Cintia / Ertekin, Ozlem / Heid, Sussane / Seyferth, Stefan / Soria, Gastón / Mariano Correa, N. / Leal-Egaña, Aldo / Boccaccini, Aldo R.

Journal of colloid and interface science. 2022 Aug. 25,

2022

Abstract: The efficacy of chemotherapeutic procedures relies on delivering proper concentrations of anti-cancer drugs in the tumor surroundings, so as to prevent potential side effects on healthy tissues. Novel drug carrier platforms should not just be able to ... ...

Abstract	The efficacy of chemotherapeutic procedures relies on delivering proper concentrations of anti-cancer drugs in the tumor surroundings, so as to prevent potential side effects on healthy tissues. Novel drug carrier platforms should not just be able to deliver anticancer molecules, but also allow for adjustements in the way these drugs are administered to the patients. We developed a system for delivering water-insoluble drugs, based on the use of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or bis(2-ethylhexyl) sulfosuccinate benzyl-n-hexadecyldimethylammonium (BHD-AOT), embedded into oxidized alginate-gelatin (ADA/Gel) hydrogel, emulating a patch for topic applications. After being loaded with curcumin, cancer cells such as human colorectal adenocarcinoma (HCT116 and DLD-1) and melanoma cell lines (MEL501), and non-malignant cells such as mammary epithelial cell lines (NMuMG) and embryonal fibroblasts (NIH 3T3 or NEO cells) were analyzed for biocompatibility and cytotoxic effects. The results show that the proposed system can load comparatively higher concentrations of the drug (with respect to other nano/microcarriers in the literature), and that it can enhance the likelihood of the drug being uptaken by cancer cells instead of non-malignant cells. These assays were complemented by diffusion studies across the stratum corneum of rat skin, with the aim of determining the system’s efficiency during topical application. Finally, the stability of the patch was tested after lyophilization to determine its potential pharmaceutical use. As a whole, the combined system represents a highly reliable and robust method for embedding and delivering complex insoluble chemotherapeutical molecules, and it is less invasive than other alternative methods in the literature.
Keywords	adenocarcinoma ; biocompatibility ; curcumin ; cytotoxicity ; drug carriers ; drugs ; epithelial cells ; fibroblasts ; freeze drying ; humans ; hydrogels ; melanoma ; oxidation ; rats ; topical application ; water solubility
Language	English
Dates of publication	2022-0825
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	241597-5
ISSN	1095-7103 ; 0021-9797
ISSN (online)	1095-7103
ISSN	0021-9797
DOI	10.1016/j.jcis.2022.08.163
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Article ; Online: Correction: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

Martino, Julieta / Siri, Sebastián Omar / Calzetta, Nicolás Luis / Paviolo, Natalia Soledad / Garro, Cintia / Pansa, Maria F / Carbajosa, Sofía / Brown, Aaron C / Bocco, José Luis / Gloger, Israel / Drewes, Gerard / Madauss, Kevin P / Soria, Gastón / Gottifredi, Vanesa

eLife

2023 Volume 12

Language	English
Publishing date	2023-11-14
Publishing country	England
Document type	Published Erratum
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.94414
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Article ; Online: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

eLife

2023 Volume 12

Abstract: The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2- ... ...

Abstract	The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2-deficient cells. In contrast, here we show that inhibiting ROCK in BRCA2-deficient cells triggers SL independently from acute replication stress. Such SL is preceded by polyploidy and binucleation resulting from cytokinesis failure. Such initial mitosis abnormalities are followed by other M phase defects, including anaphase bridges and abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate that cytokinesis failure triggers mitotic abnormalities and SL in BRCA2-deficient cells. Furthermore, the prevention of mitotic entry by depletion of Early mitotic inhibitor 1 (EMI1) augmented the survival of BRCA2-deficient cells treated with ROCK inhibitors, thus reinforcing the association between M phase and cell death in BRCA2-deficient cells. This novel SL differs from the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2-deficient cells.
MeSH term(s)	Anaphase ; DNA Damage ; Mitosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Synthetic Lethal Mutations ; rho-Associated Kinases/antagonists & inhibitors ; BRCA2 Protein/genetics ; Humans
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; rho-Associated Kinases (EC 2.7.11.1) ; BRCA2 Protein
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.80254
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Article: Egg perivitelline fluid of the invasive snail

Giglio, Matías / Garro, Cintia / Caviedes-Vidal, Enrique / Heras, Horacio

PeerJ

2018 Volume 6, Page(s) e5314

Abstract: Background: Species beloging to the genus : Methods: Carbohydrate digestion by intestinal disaccharidases (sucrase-isomaltase and maltase-glucoamylase) was evaluated : Results: Perivitelline fluid affected mice displayed significant morphological ... ...

Abstract	Background: Species beloging to the genus Methods: Carbohydrate digestion by intestinal disaccharidases (sucrase-isomaltase and maltase-glucoamylase) was evaluated Results: Perivitelline fluid affected mice displayed significant morphological changes in the small intestine epithelium inducing the appearance of shorter and wider villi as well as fused villi. This resulted in a diminished absorptive surface, notably in the proximal portion Discussion: Oral administration of apple snail PVF to mice adversely alters gut morphophysiology by reducing the intestinal absorptive surface, affecting enzymes of sugar metabolism and increasing the absorption rate of nutrients without affecting the relative contribution of the absorption pathways or gut permeability. These results further support the role of PVF in passive anti-predator defenses in
Language	English
Publishing date	2018-10-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2703241-3
ISSN	2167-8359
ISSN	2167-8359
DOI	10.7717/peerj.5314
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Article ; Online: Small intestinal epithelial permeability to water-soluble nutrients higher in passerine birds than in rodents.

Garro, Cintia / Brun, Antonio / Karasov, William H / Caviedes-Vidal, Enrique

Journal of animal physiology and animal nutrition

2018 Volume 102, Issue 6, Page(s) 1766–1773

Abstract: In the small intestine transcellular and paracellular pathways are implicated in water-soluble nutrient absorption. In small birds the paracellular pathway is quantitatively important while transcellular pathway is much more important in terrestrial ... ...

Abstract	In the small intestine transcellular and paracellular pathways are implicated in water-soluble nutrient absorption. In small birds the paracellular pathway is quantitatively important while transcellular pathway is much more important in terrestrial mammals. However, there is not a clear understanding of the mechanistic underpinnings of the differences among taxa. This study was aimed to test the hypothesis that paracellular permeability in perfused intestinal segments is higher in passerine birds than rodents. We performed in situ intestinal perfusions on individuals of three species of passerine birds (Passer domesticus, Taeniopygia guttata and Furnarius rufus) and two species of rodents (Mus musculus and Meriones ungiculatus). Using radio-labelled molecules, we measured the uptake of two nutrients absorbed by paracellular and transcellular pathways (L-proline and 3-O-methyl-D-glucose) and one carbohydrate that has no mediated transport (L-arabinose). Birds exhibited ~2 to ~3 times higher L-arabinose clearance per cm
MeSH term(s)	3-O-Methylglucose/pharmacokinetics ; Animals ; Arabinose/pharmacokinetics ; Biological Transport ; Gerbillinae/physiology ; Intestinal Mucosa/physiology ; Mice/physiology ; Passeriformes/physiology ; Permeability ; Proline/pharmacokinetics ; Species Specificity
Chemical Substances	3-O-Methylglucose (146-72-5) ; Proline (9DLQ4CIU6V) ; Arabinose (B40ROO395Z)
Language	English
Publishing date	2018-08-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	232729-6
ISSN	1439-0396 ; 0044-3565 ; 0931-2439
ISSN (online)	1439-0396
ISSN	0044-3565 ; 0931-2439
DOI	10.1111/jpn.12969
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Article ; Online: Topical systems for the controlled release of antineoplastic Drugs: Oxidized Alginate-Gelatin Hydrogel/Unilamellar vesicles.

Stagnoli, Soledad / Garro, Cintia / Ertekin, Ozlem / Heid, Susanne / Seyferth, Stefan / Soria, Gastón / Mariano Correa, N / Leal-Egaña, Aldo / Boccaccini, Aldo R

Journal of colloid and interface science

2022 Volume 629, Issue Pt A, Page(s) 1066–1080

Abstract	The efficacy of chemotherapeutic procedures relies on delivering proper concentrations of anti-cancer drugs in the tumor surroundings, so as to prevent potential side effects on healthy tissues. Novel drug carrier platforms should not just be able to deliver anticancer molecules, but also allow for adjustements in the way these drugs are administered to the patients. We developed a system for delivering water-insoluble drugs, based on the use of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or bis(2-ethylhexyl) sulfosuccinate benzyl-n-hexadecyldimethylammonium (BHD-AOT), embedded into oxidized alginate-gelatin (ADA/Gel) hydrogel, emulating a patch for topic applications. After being loaded with curcumin, cancer cells such as human colorectal adenocarcinoma (HCT116 and DLD-1) and melanoma cell lines (MEL501), and non-malignant cells such as mammary epithelial cell lines (NMuMG) and embryonal fibroblasts (NIH 3T3 or NEO cells) were analyzed for biocompatibility and cytotoxic effects. The results show that the proposed system can load comparatively higher concentrations of the drug (with respect to other nano/microcarriers in the literature), and that it can enhance the likelihood of the drug being uptaken by cancer cells instead of non-malignant cells. These assays were complemented by diffusion studies across the stratum corneum of rat skin, with the aim of determining the system's efficiency during topical application. Finally, the stability of the patch was tested after lyophilization to determine its potential pharmaceutical use. As a whole, the combined system represents a highly reliable and robust method for embedding and delivering complex insoluble chemotherapeutical molecules, and it is less invasive than other alternative methods in the literature.
MeSH term(s)	Humans ; Rats ; Animals ; Hydrogels/pharmacology ; Gelatin ; Unilamellar Liposomes ; Alginates ; Delayed-Action Preparations/pharmacology ; Antineoplastic Agents/pharmacology ; Drug Delivery Systems/methods
Chemical Substances	Hydrogels ; Gelatin (9000-70-8) ; Unilamellar Liposomes ; Alginates ; Delayed-Action Preparations ; Antineoplastic Agents
Language	English
Publishing date	2022-08-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	241597-5
ISSN	1095-7103 ; 0021-9797
ISSN (online)	1095-7103
ISSN	0021-9797
DOI	10.1016/j.jcis.2022.08.163
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Article: Small intestinal epithelial permeability to water‐soluble nutrients higher in passerine birds than in rodents

Garro, Cintia / Antonio Brun / William H. Karasov / Enrique Caviedes‐Vidal

Journal of animal physiology and animal nutrition. 2018 Dec., v. 102, no. 6

2018

Abstract: In the small intestine transcellular and paracellular pathways are implicated in water‐soluble nutrient absorption. In small birds the paracellular pathway is quantitatively important while transcellular pathway is much more important in terrestrial ... ...

Abstract	In the small intestine transcellular and paracellular pathways are implicated in water‐soluble nutrient absorption. In small birds the paracellular pathway is quantitatively important while transcellular pathway is much more important in terrestrial mammals. However, there is not a clear understanding of the mechanistic underpinnings of the differences among taxa. This study was aimed to test the hypothesis that paracellular permeability in perfused intestinal segments is higher in passerine birds than rodents. We performed in situ intestinal perfusions on individuals of three species of passerine birds (Passer domesticus, Taeniopygia guttata and Furnarius rufus) and two species of rodents (Mus musculus and Meriones ungiculatus). Using radio‐labelled molecules, we measured the uptake of two nutrients absorbed by paracellular and transcellular pathways (L‐proline and 3–O–methyl–D‐glucose) and one carbohydrate that has no mediated transport (L‐arabinose). Birds exhibited ~2 to ~3 times higher L‐arabinose clearance per cm² epithelium than rodents. Moreover, paracellular absorption accounted for proportionally more of 3–O–methyl–D‐glucose and L‐proline absorption in birds than in rodents. These differences could be explained by differences in intestinal permeability and not by other factors such as increased retention time or higher intestinal nominal surface area. Furthermore, analysis of our results and all other existing data on birds, bats and rodents shows that insectivorous species (one bird, two bats and a rodent) had only 30% of the clearance of L‐arabinose of non‐insectivorous species. This result may be explained by weaker natural selection for high paracellular permeability in animal‐ than in plant‐consumers. Animal‐consumers absorb less sugar and more amino acids, whose smaller molecular size allow them to traverse the paracellular pathway more extensively and faster than glucose.
Keywords	Chiroptera ; Meriones ; Mus musculus ; Passer domesticus ; Taeniopygia guttata ; absorption ; arabinose ; birds ; epithelium ; glucose ; insectivores ; molecular weight ; natural selection ; nutrient uptake ; nutrients ; permeability ; proline ; radiolabeling ; rodents ; small intestine ; surface area ; water solubility
Language	English
Dates of publication	2018-12
Size	p. 1766-1773.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ISSN	0931-2439
DOI	10.1111/jpn.12969
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency.

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

2023 Volume 67, Page(s) 100932

Abstract: BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of ... ...

Abstract	BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine's target responsible for its BRCA2-linked SL induction. Additional confirmatory evidence was obtained by using the highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, thus setting the ground for future therapeutic alternatives to PARP inhibitors.
MeSH term(s)	Humans ; Deoxycytidine Kinase/genetics ; Deoxycytidine Kinase/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Nucleotides/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; BRCA2 Protein/genetics
Chemical Substances	Deoxycytidine Kinase (EC 2.7.1.74) ; Poly(ADP-ribose) Polymerase Inhibitors ; Antineoplastic Agents ; Nucleotides ; Protein Kinase Inhibitors ; BRCA2 protein, human ; BRCA2 Protein
Language	English
Publishing date	2023-01-22
Publishing country	Scotland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1474513-6
ISSN	1532-2084 ; 1368-7646
ISSN (online)	1532-2084
ISSN	1368-7646
DOI	10.1016/j.drup.2023.100932
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