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Article ; Online: MicroRNAs and the Response of Prostate Cancer to Anti-Cancer Drugs.

Pennati, Marzia / Folini, Marco / Gandellini, Paolo / Zaffaroni, Nadia

2015 Volume 17, Issue 3, Page(s) 257–265

Abstract: Despite considerable advances in early diagnosis, prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men in western countries. In fact, although efficient therapies exist for early-stage disease, the treatment of advanced ... ...

Abstract	Despite considerable advances in early diagnosis, prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men in western countries. In fact, although efficient therapies exist for early-stage disease, the treatment of advanced PCa remains unsuccessful mainly due to its poor responsiveness to anti-cancer agents. This evidence underlines the urgent need for the development of novel and more effective therapeutic approaches. In this context, the documented dysregulation of microRNAs (miRNAs)--which are short non-coding RNAs that regulate gene expression at post-transcriptional level- in PCa, together with their potential to simultaneously regulate multiple oncogenic/ tumor-suppressive pathways, has stimulated interest in defining a functional association between altered expression of specific miRNAs and the response of PCa to anti-cancer agents. The purpose of this review is to provide an overview on PCa-related miRNAs as potential novel therapeutic targets/tools, with a special focus on the role that they may play in conditioning the responsiveness of PCa to anti-cancer drugs.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; MicroRNAs/genetics ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Treatment Outcome
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; MicroRNAs
Language	English
Publishing date	2015-03-09
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2064859-5
ISSN	1873-5592 ; 1389-4501
ISSN (online)	1873-5592
ISSN	1389-4501
DOI	10.2174/1389450116666150316223341
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Article: Strategies to Strike Survival Networks in Cancer.

Pennati, Marzia / Cimino-Reale, Graziella / Gatti, Laura / Cassinelli, Giuliana

Critical reviews in oncogenesis

2016 Volume 21, Issue 3-4, Page(s) 269–308

Abstract: The machinery that maintains cellular and tissue homeostasis in a healthy individual is recruited and hijacked by cancer cells to support tumor growth and progression. Activation of often unpredictable alternative or complementary signaling pathways ... ...

Abstract	The machinery that maintains cellular and tissue homeostasis in a healthy individual is recruited and hijacked by cancer cells to support tumor growth and progression. Activation of often unpredictable alternative or complementary signaling pathways allows cancer cells to bypass the intrinsic self-destructive machinery and the limited replicative potential present in every cell for correct homeostasis maintenance. Therefore, evasion/resistance to apoptosis/cell death, self-sufficiency in growth/survival signals, and limitless replicative potential remain undoubted hallmarks of cancer, contributing to drug resistance. Herein, we specifically review antitumor strategies involving agents targeting deregulated receptor tyrosine kinases, selected epigenetic modifications, the ubiquitin-proteasome system, the unfolded protein response, the apoptotic pathway, and peculiar nucleic acid structures, with the aim of highlighting the mechanisms underlying favorable drug interaction. In this context, we focus on preclinical studies that have already been translated into clinical investigation. Particular emphasis is devoted to strategies effective in solid tumors because of the peculiarity and distinctive features of solid tumors in terms of drug delivery and relative to the impact of the tumor microenvironment.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Cell Survival/drug effects ; Drug Delivery Systems ; Drug Resistance, Neoplasm ; Epigenesis, Genetic/drug effects ; G-Quadruplexes/drug effects ; Humans ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/physiopathology ; Signal Transduction/drug effects
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2016-12-01
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1036388-9
ISSN	0893-9675
ISSN	0893-9675
DOI	10.1615/CritRevOncog.2016016966
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Article ; Online: Dissecting the role of microRNAs in prostate cancer metastasis: implications for the design of novel therapeutic approaches.

Doldi, Valentina / Pennati, Marzia / Forte, Barbara / Gandellini, Paolo / Zaffaroni, Nadia

Cellular and molecular life sciences : CMLS

2016 Volume 73, Issue 13, Page(s) 2531–2542

Abstract: Metastatic prostate cancer is a lethal disease that remains incurable despite the recent approval of new drugs, thus making the development of alternative treatment approaches urgently needed. A more precise understanding of the molecular mechanisms ... ...

Abstract	Metastatic prostate cancer is a lethal disease that remains incurable despite the recent approval of new drugs, thus making the development of alternative treatment approaches urgently needed. A more precise understanding of the molecular mechanisms underlying prostate cancer dissemination could lead to the identification of novel therapeutic targets for the design of efficient anti-metastatic strategies. MicroRNA (miRNAs) are endogenous, small non-coding RNA molecules acting as key regulators of gene expression at post-transcriptional level. It has been clearly established that altered miRNA expression is a common hallmark of cancer. In addition, emerging evidence suggests their direct involvement in the metastatic cascade. In this review, we present a comprehensive overview of the data generated in experimental tumor models indicating that specific miRNAs may impinge on the different stages of prostate cancer metastasis, including (i) the regulation of epithelial-to-mesenchymal transition and cell migration/invasion, (ii) the interplay between cancer cells and the surrounding stroma, (iii) the control of angiogenesis, (iv) the regulation of anoikis, and (v) the colonization of distant organs. Moreover, we show preliminary evidence of the clinical relevance of some of these miRNAs, in terms of association with tumor aggressiveness/dissemination and clinical outcome, as emerged from translation studies carried out in prostate cancer patient cohorts. We also discuss the potential and the current limitations of manipulating metastasis-related miRNAs, by mimicking or inhibiting them, as a strategy for the development of novel therapeutic approaches for the advanced disease.
MeSH term(s)	Animals ; Cell Movement ; Epithelial-Mesenchymal Transition ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; MicroRNAs/analysis ; MicroRNAs/genetics ; Neoplasm Metastasis/genetics ; Neoplasm Metastasis/pathology ; Neoplasm Metastasis/therapy ; Prostate/blood supply ; Prostate/pathology ; Prostatic Neoplasms/blood supply ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/therapy
Chemical Substances	MicroRNAs
Language	English
Publishing date	2016-03-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-016-2176-3
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Article: miR-34a-Mediated Survivin Inhibition Improves the Antitumor Activity of Selinexor in Triple-Negative Breast Cancer.

Martini, Silvia / Zuco, Valentina / Tortoreto, Monica / Percio, Stefano / Campi, Elisa / El Bezawy, Rihan / Doldi, Valentina / Landesman, Yosef / Pennati, Marzia / Zaffaroni, Nadia

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 6

Abstract: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Here, we pursued a combinatorial therapeutic approach to enhance the activity of selinexor, the first-in-class XPO1 inhibitor, by miR-34a ectopic expression ... ...

Abstract	Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Here, we pursued a combinatorial therapeutic approach to enhance the activity of selinexor, the first-in-class XPO1 inhibitor, by miR-34a ectopic expression in human TNBC experimental models. Anti-proliferative activity induced by selinexor and miR-34a expression, singly and in combination, was evaluated by MTS assay and cell counting. The effect of treatments on survivin and apoptosis-related proteins was assessed by western blotting and ELISA. The antitumor and toxic effects of individual and combined treatments were evaluated on TNBC orthotopic xenografts in SCID mice. Selinexor consistently showed anti-proliferative activity, although to a variable extent, in the different TNBC cell lines and caused the impairment of survivin expression and intracellular distribution, accompanied by apoptosis induction. Consistent with in vitro data, the XPO1 inhibitor variably affected the growth of TNBC orthotopic xenografts. miR-34a cooperated with selinexor to reduce survivin expression and improved its anti-proliferative activity in TNBC cells. Most importantly, miR-34a expression markedly enhanced selinexor antitumor activity in the less sensitive TNBC xenograft model, in absence of toxicity. Our data form a solid foundation for promoting the use of a miR-34a-based approach to improve the therapeutic efficacy of selinexor in TNBC patients.
Language	English
Publishing date	2021-05-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14060523
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Article ; Online: Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer.

Spinello, Angelo / Martini, Silvia / Berti, Federico / Pennati, Marzia / Pavlin, Matic / Sgrignani, Jacopo / Grazioso, Giovanni / Colombo, Giorgio / Zaffaroni, Nadia / Magistrato, Alessandra

European journal of medicinal chemistry

2019 Volume 168, Page(s) 253–262

Abstract: Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies ... ...

Abstract	Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance.
MeSH term(s)	Allosteric Regulation/drug effects ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Aromatase/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Design ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Molecular Dynamics Simulation ; Molecular Structure ; Structure-Activity Relationship
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Aromatase (EC 1.14.14.1)
Language	English
Publishing date	2019-02-13
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2019.02.045
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Article ; Online: Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents.

Beretta, Giovanni Luca / Cassinelli, Giuliana / Pennati, Marzia / Zuco, Valentina / Gatti, Laura

European journal of medicinal chemistry

2017 Volume 142, Page(s) 271–289

Abstract: Resistance to conventional and target specific antitumor drugs still remains one of the major cause of treatment failure and patience death. This condition often involves ATP-binding cassette (ABC) transporters that, by pumping the drugs outside from ... ...

Abstract	Resistance to conventional and target specific antitumor drugs still remains one of the major cause of treatment failure and patience death. This condition often involves ATP-binding cassette (ABC) transporters that, by pumping the drugs outside from cancer cells, attenuate the potency of chemotherapeutics and negatively impact on the fate of anticancer therapy. In recent years, several tyrosine kinase inhibitors (TKIs) (e.g., imatinib, nilotinib, dasatinib, ponatinib, gefitinib, erlotinib, lapatinib, vandetanib, sunitinib, sorafenib) have been reported to interact with ABC transporters (e.g., ABCB1, ABCC1, ABCG2, ABCC10). This finding disclosed a very complex scenario in which TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, affinity for transporters and types of co-administered agents. In this context, in-depth investigation on TKI chemosensitizing functions might provide a strong rationale for combining TKIs and conventional therapeutics in specific malignancies. The reposition of TKIs as antagonists of ABC transporters opens a new way towards anticancer therapy and clinical strategies aimed at counteracting drug resistance. This review will focus on some paradigmatic examples of the complex and not yet fully elucidated interaction between clinical available TKIs (e.g. BCR-ABL, EGFR, VEGFR inhibitors) with the main ABC transporters implicated in multidrug resistance.
Language	English
Publishing date	2017-12-15
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2017.07.062
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Article ; Online: Selinexor Sensitizes TRAIL-R2-Positive TNBC Cells to the Activity of TRAIL-R2xCD3 Bispecific Antibody.

Martini, Silvia / Figini, Mariangela / Croce, Aurora / Frigerio, Barbara / Pennati, Marzia / Gianni, Alessandro Massimo / De Marco, Cinzia / Daidone, Maria Grazia / Argueta, Christian / Landesman, Yosef / Zaffaroni, Nadia / Satta, Alessandro

Cells

2020 Volume 9, Issue 10

Abstract: Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific ... ...

Abstract	Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirecting CD3
MeSH term(s)	Antibodies, Bispecific/physiology ; Cell Line, Tumor ; Female ; Humans ; Hydrazines/pharmacology ; Hydrazines/therapeutic use ; Triazoles/pharmacology ; Triazoles/therapeutic use ; Triple Negative Breast Neoplasms/drug therapy
Chemical Substances	Antibodies, Bispecific ; Hydrazines ; Triazoles ; selinexor (31TZ62FO8F)
Language	English
Publishing date	2020-10-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9102231
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Article ; Online: miR-34a-Mediated Survivin Inhibition Improves the Antitumor Activity of Selinexor in Triple-Negative Breast Cancer

Silvia Martini / Valentina Zuco / Monica Tortoreto / Stefano Percio / Elisa Campi / Rihan El Bezawy / Valentina Doldi / Yosef Landesman / Marzia Pennati / Nadia Zaffaroni

Pharmaceuticals, Vol 14, Iss 523, p

2021 Volume 523

Abstract	Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Here, we pursued a combinatorial therapeutic approach to enhance the activity of selinexor, the first-in-class XPO1 inhibitor, by miR-34a ectopic expression in human TNBC experimental models. Anti-proliferative activity induced by selinexor and miR-34a expression, singly and in combination, was evaluated by MTS assay and cell counting. The effect of treatments on survivin and apoptosis-related proteins was assessed by western blotting and ELISA. The antitumor and toxic effects of individual and combined treatments were evaluated on TNBC orthotopic xenografts in SCID mice. Selinexor consistently showed anti-proliferative activity, although to a variable extent, in the different TNBC cell lines and caused the impairment of survivin expression and intracellular distribution, accompanied by apoptosis induction. Consistent with in vitro data, the XPO1 inhibitor variably affected the growth of TNBC orthotopic xenografts. miR-34a cooperated with selinexor to reduce survivin expression and improved its anti-proliferative activity in TNBC cells. Most importantly, miR-34a expression markedly enhanced selinexor antitumor activity in the less sensitive TNBC xenograft model, in absence of toxicity. Our data form a solid foundation for promoting the use of a miR-34a-based approach to improve the therapeutic efficacy of selinexor in TNBC patients.
Keywords	negative breast cancer ; selinexor ; miR-34a ; survivin ; xenografts ; apoptosis ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	610
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers.

Pavlin, Matic / Spinello, Angelo / Pennati, Marzia / Zaffaroni, Nadia / Gobbi, Silvia / Bisi, Alessandra / Colombo, Giorgio / Magistrato, Alessandra

Scientific reports

2018 Volume 8, Issue 1, Page(s) 649

Abstract: Somatic mutations of the Estrogen Receptor α (ERα) occur with an up to 40% incidence in ER sensitive breast cancer (BC) patients undergoing prolonged endocrine treatments. These polymorphisms are implicated in acquired resistance, disease relapse, and ... ...

Abstract	Somatic mutations of the Estrogen Receptor α (ERα) occur with an up to 40% incidence in ER sensitive breast cancer (BC) patients undergoing prolonged endocrine treatments. These polymorphisms are implicated in acquired resistance, disease relapse, and increased mortality rates, hence representing a current major clinical challenge. Here, multi-microseconds (12.5 µs) molecular dynamics simulations revealed that recurrent ERα polymorphisms (i. e. L536Q, Y537S, Y537N, D538G) (mERα) are constitutively active in their apo form and that they prompt the selection of an agonist (active)-like conformation even upon antagonists binding. Interestingly, our simulations rationalize, for the first time, the efficacy profile of (pre)clinically used Selective Estrogen Receptor Modulators/Downregulators (SERMs/SERDs) against these variants, enlightening, at atomistic level of detail, the key common structural traits needed by drugs able to effectively fight refractory BC types. This knowledge represents a key advancement for mechanism-based therapeutics targeting resistant ERα isoforms, potentially allowing the community to move a step closer to 'precision medicine' calibrated on patients' genetic profiles and disease progression.
MeSH term(s)	Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Estrogen Receptor Antagonists/chemistry ; Estrogen Receptor Antagonists/pharmacology ; Estrogen Receptor alpha/antagonists & inhibitors ; Estrogen Receptor alpha/chemistry ; Estrogen Receptor alpha/genetics ; Female ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Polymorphism, Single Nucleotide/drug effects ; Protein Structure, Secondary
Chemical Substances	ESR1 protein, human ; Estrogen Receptor Antagonists ; Estrogen Receptor alpha
Language	English
Publishing date	2018-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-17364-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: miR-342 overexpression results in a synthetic lethal phenotype in BRCA1-mutant HCC1937 breast cancer cells.

Crippa, Elisabetta / Folini, Marco / Pennati, Marzia / Zaffaroni, Nadia / Pierotti, Marco A / Gariboldi, Manuela

Oncotarget

2016 Volume 7, Issue 14, Page(s) 18594–18604

Abstract: Expression of miR-342 has been strongly correlated with estrogen receptor (ER) status in breast cancer, where it is highest in ER-positive and lowest in triple-negative tumors. We investigated the effects of miR-342 transfection in the triple-negative ... ...

Abstract	Expression of miR-342 has been strongly correlated with estrogen receptor (ER) status in breast cancer, where it is highest in ER-positive and lowest in triple-negative tumors. We investigated the effects of miR-342 transfection in the triple-negative breast cancer cell lines MDA-MB-231 and HCC1937, the latter carrying a germ-line BRCA1 mutation. Reconstitution of miR-342 led to caspase-dependent induction of apoptosis only in HCC1937 cells, while overexpression of wild-type BRCA1 in HCC1937 cells counteracted miR-342-mediated induction of apoptosis, suggesting that miR-342 overexpression and the lack of functional BRCA1 result in a synthetic lethal phenotype. Moreover, siRNA-mediated depletion of BRCA1 in MDA-MB-231 cells expressing the wild-type protein led to apoptosis upon transfection with miR-342. Using an in silico approach and a luciferase reporter system, we identified and functionally validated the Baculoviral IAP repeat-containing 6 gene (BIRC6), which encodes the anti-apoptotic factor Apollon/BRUCE, as a target of miR-342. In our model, BIRC6 likely acts as a determinant of the miRNA-dependent induction of apoptosis in BRCA1-mutant HCC1937 cells. Together, our findings suggest a tumor-suppressive function of miR-342 that could be exploited in the treatment of a subset of BRCA1-mutant hereditary breast cancers.
MeSH term(s)	Apoptosis/genetics ; BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; Cell Line, Tumor ; Female ; Humans ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Mutation ; Phenotype ; Transfection ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; MicroRNAs
Language	English
Publishing date	2016-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.7617
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