Publications by authors named "Serena Pillozzi"

47 Publications

Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives.

Cancers (Basel) 2021 Mar 4;13(5). Epub 2021 Mar 4.

Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy.

The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.
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http://dx.doi.org/10.3390/cancers13051091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961559PMC
March 2021

Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

Cancers (Basel) 2021 Feb 18;13(4). Epub 2021 Feb 18.

Clinical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy.

Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients.

Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group.

Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction ( = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11-0.77) = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13-0.84) = 0.020].

Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response.
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http://dx.doi.org/10.3390/cancers13040860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922597PMC
February 2021

rearrangements are uncommon in biliary tract cancers.

Oncol Lett 2020 Dec 1;20(6):316. Epub 2020 Oct 1.

Operative Unit of Pathologic Anatomy, Santa Maria delle Croci Hospital, I-48121 Ravenna, Italy.

Biliary tract cancers (BTCs) are a pool of diseases with poor prognosis and there is no orphan drug available. Currently, no molecular targets have been tested as druggable oncogenic drivers. C-ros oncogene 1 () rearrangements have been previously described in various tumors, including BTCs; however, data regarding their incidence and biological significance are controversial. Therefore, a retrospective multicenter study was performed to assess the incidence of rearrangements in BTCs by means of immunohistochemistry and fluorescence hybridization (FISH). The present study failed to demonstrate ROS1 expression in a multicenter series of 150 cases with BTCs and revealed that D4D6 was the most specific clone compared with other ROS1 primary antibodies, namely PA1-30318 and EPMGHR2. Notably, negative results obtained with D4D6 completely matched to data sorted out by FISH analysis, thus confirming a lack of gene rearrangements in BTCs and false positive results when PA1-30318 and EPMGHR2 clones were used. These results suggest that rearrangements may not be targets for molecular therapy of BTCs with specific inhibitors.
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http://dx.doi.org/10.3892/ol.2020.12179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590438PMC
December 2020

Detection of PIK3CA E545A mutation in circulating tumor DNA of a patient affected by uterine carcinosarcoma.

Anticancer Drugs 2020 09;31(8):880-883

Department of Medical Oncology, Careggi University Hospital.

Uterine carcinosarcomas are biphasic neoplasms consisting of mixed epithelial and mesenchymal elements, representing less than 5% of all uterine malignancies. Carcinosarcomas are rare, although the most common cause of uterine cancer-specific death. Few information is available on the pathogenesis, and molecular characterization is poorly investigated. Consequently, the treatment has not changed over the last years and is far too being tailored, consisting of surgery and traditional chemotherapy and radiotherapy. Molecular characterization of liquid biopsy by circulating tumor DNA (ctDNA)/circulating cell-free DNA (ccfDNA) evaluation in a patient with uterine carcinosarcoma. Here, we describe a case report of an 83-year-old woman with carcinosarcomas, stage T3aN0M0. Cancer cells did not express estrogen nor progesterone receptors, while p53 and p16 were positive. Molecular characterization of ccfDNA and of ctDNA was performed by quantitative PCR, amplification-refractory mutation system technology. The presence of phosphatidylInositol-4,5-bisphosphate 3-Kinase catalytic subunit alpha p.E545A mutation was detected in plasma. This approach may suggest the use of liquid biopsy and the development of specific targeted therapy for precision personalized medicine even in rare carcinosarcomas.
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http://dx.doi.org/10.1097/CAD.0000000000000959DOI Listing
September 2020

Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective.

Int J Mol Sci 2020 Jun 30;21(13). Epub 2020 Jun 30.

Clinical Oncology Unit, AOU Careggi, 50134 Firenze, Italy.

Systemic treatment of renal cancer (RCC) has undergone remarkable changes over the past 20 years with the introduction of immunotherapeutic agents targeting programmed cell death (PD-1)/programmed death-ligand 1 (PD-L1) axis, as a single-agent or combined with anti-CTLA-4 monoclonal antibodies (MoAbs) or a multi-target vascular endothelial growth factor-(VEGF) tyrosine kinase inhibitor (TKI). In this paper, we review the main evidence on the use of Immune Checkpoint Inhibitors (ICIs) for RCC treatment from the first demonstration of activity of a nivolumab single agent in a phase I trial to the novel combination strategies (anti-PD-1 plus anti-CTLA4 or anti-PD-1 plus TKI). In addition, we discuss the use of anti-PD-1/PD-L1 agents in patients with non-clear cells and rare histological subtype RCC. Then, we critically examine the current findings in biomarkers that have been proposed to be prognostic or predictive to the response of immunotherapy including immune gene expression signature, B7-H1 expression, PBRM1 loss of function, PD-L1 expression, frame shift indel count, mutations in bromodomain-containing genes in patients with MiT family translocation RCC (tRCC), high expression of the T-effector gene signature, and a high myeloid inflammation gene expression pattern. To date, a single biomarker as a predictor of response has not been established. Since the dynamic behavior of the immune response and the different impact of ICI treatment on patients with specific RCC subtypes, the integration of multiple biomarkers and further validation in clinical trials are needed.
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http://dx.doi.org/10.3390/ijms21134691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369721PMC
June 2020

Somatostatin analogs in pregnant patients with neuroendocrine tumor.

Anticancer Drugs 2020 11;31(10):1096-1098

Medical Oncology Unit, Careggi University Hospital, Firenze.

Somatostatine analogs (SSAs) are currently indicated in the treatment of acromegaly and neuroendocrine tumors (NETs). Actually, pregnancy in patients with acromegaly and NETs does not represent an exceptional event because reproductive behavior has changed in the last decades and patients with NETs show more frequently long-term survival. The safety profile of SSAs during pregnancy is still controversial. Concerning acromegaly, based on case reports and series, SSAs administration during pregnancy seems to be relatively well tolerated. Concerning patients with NETs, up to date only one patient with NET receiving SSA during pregnancy has been reported in literature. We report two cases of gastroenteropancreatic-NET patients receiving SSA lanreotide for the entire course of their pregnancy, with favorable outcomes for both mothers and babies. Our experience supports the possibility to continue safely SSA lanreotide during pregnancy in patients with NET.
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http://dx.doi.org/10.1097/CAD.0000000000000967DOI Listing
November 2020

Mutational profile in circulating tumor DNA in a patient affected by low-risk endometrial cancer: predictable tool of relapse?

Anticancer Drugs 2020 11;31(10):1091-1095

Clinical Oncology Unit,, Careggi University Hospital, Florence.

Endometrial cancer is the commonest gynecological cancer, the majority is endometrioid type, diagnosed at an early stage with 69-88% 5-year survival. Low-grade endometrial cancers have low recurrence rates and often do not receive adjuvant therapy; however, a subset of these patients will have poor outcomes and would benefit from adjuvant treatment has been challenging. We evaluate the circulating cell-free DNA (ccfDNA) in a patient with low-risk endometrial cancer in order to identify the presence of molecular markers associated with risk of recurrence. The evaluation of mutation profile was performed by next-generation sequencing (NGS) in primary tumor formalin-fixed paraffin-embedded (FFPE) tissue and in circulating tumor DNA (ctDNA). We identified a specific mutational profile in ctDNA, different from primary tumor tissue suggesting that the clone involved in the relapse may be different in comparison to the most represented in the primary tumor. These findings open new prospective and new wonderings. The molecular characterization of tissue may be useful for setting new target personalized therapy even in the treatment of endometrial cancer, moreover, endometrial cancer at low risk should be not underestimated for the incidence of relapse, and for this evaluation the molecular characterization may be useful. Moreover, these results suggest that the single analysis of primary tumors may be not sufficient for setting a specific personalized therapy targeted to avoid the relapse but may be necessary to join the molecular characterization of liquid biopsy to primary tissue.
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http://dx.doi.org/10.1097/CAD.0000000000000963DOI Listing
November 2020

Identification of a Gene Panel for Endometrioid Endometrial Cancer: a Possible Prognostic Value?

Reprod Sci 2020 02 6;27(2):592-598. Epub 2020 Jan 6.

Department of Experimental and Clinical Medicine, University of Florence, 50134, Florence, Italy.

The incidence of endometrial cancer (EC) is increasing in developed countries. The most frequent is the endometrioid subtype with usually good prognosis; nevertheless, some cases escape this paradigm and may have recurrence. A recent study from The Cancer Genome Atlas suggested to implement the EC analysis by molecular profile for improving diagnosis, prognosis, and therapeutic treatment. The present preliminary study was performed on 15 G3 endometrioid endometrial cancers (G3 EEC) for the identification of somatic mutations in a panel of specific exons in selected genes as ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, and TP53. The combined procedure, based on the Sanger sequencing and PCR-high-resolution melting analysis, allowed the identification of variations of the selected gene panel in most of patients (93%) of our cohort. The overall evaluation of mutational load exhibited that the most frequent mutated genes were PTEN (93%), followed by PIK3CA (47%) suggesting a deep involvement of PI3K pathway alteration in G3 EEC. Mutations in TP53 (27%), ARID1A (27%), POLE (13%), and at the lower level in KRAS and CTNNB1 (7%) were also observed (exclusively in FIGO III stage patients). The evaluation of the mutations of our proposed panel (ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, TP53) is suitable to improve the characterization of G3 EEC and could suggest targetable pathways for development of personalized treatments.
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http://dx.doi.org/10.1007/s43032-019-00059-8DOI Listing
February 2020

Correction to: Structural and solution chemistry, antiproliferative effects, and serum albumin binding of three pseudohalide derivatives of auranofin.

Biometals 2019 Dec;32(6):949

Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124, Pisa, Italy.

In the initial online publication, the given name of the first author was incorrectly displayed and should have read Damiano. The original article has been corrected and the proper representation of the authors' names and their affiliation is also listed here.
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http://dx.doi.org/10.1007/s10534-019-00227-yDOI Listing
December 2019

Structural and solution chemistry, antiproliferative effects, and serum albumin binding of three pseudohalide derivatives of auranofin.

Biometals 2019 12 19;32(6):939-948. Epub 2019 Nov 19.

Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124, Pisa, Italy.

Three pseudohalide analogues of the established gold drug auranofin (AF hereafter), of general formula Au(PEt)X, i.e. Au(PEt)CN, Au(PEt)SCN and Au(PEt)N (respectively denoted as AFCN, AFSCN and AFN), were prepared and characterized. The crystal structure was solved for Au(PEt)SCN highlighting the classical linear geometry of the 2-coordinate gold(I) center. The solution behaviour of the compounds was then comparatively analysed through PNMR providing evidence for an acceptable stability under physiological-like conditions. Afterward, the reaction of these gold compounds with bovine serum albumin (BSA) and consequent adduct formation was investigated by PNMR. For all the studied gold compounds, the [Au(PEt)] moiety was identified as the reactive species in metal/protein adducts formation. The cytotoxic effects of the complexes were subsequently measured in comparison to AF against a representative colorectal cancer cell line and found to be still relevant and roughly similar in the three cases though far weaker than those of AF. These results show that the nature of the anionic ligand can modulate importantly the pharmacological action of the gold-triethylphosphine moiety, affecting the cytotoxic potency. These aspects may be further explored to improve the pharmacological profiles of this family of metal complexes.
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http://dx.doi.org/10.1007/s10534-019-00224-1DOI Listing
December 2019

Data describing the effects of the Macrolide Antibiotic Clarithromycin on preclinical mouse models of Colorectal Cancer.

Data Brief 2019 Oct 22;26:104406. Epub 2019 Aug 22.

Department of Experimental and Clinical Medicine, University of Firenze, Viale GB Morgagni 50, 50134 Firenze, Italy.

Macrolide antibiotics, such as Clarithromycin (Cla), have been proven to exert anti-tumour activity in several preclinical models of different types of cancer. Cla can exert its anti-tumour effects through different mechanisms, e.g. by blocking the autophagic flux, inducing apoptosis or inhibiting tumour-induced angiogenesis. The clinical benefit of Cla in treating various tumours in combination with conventional treatment was confirmed in extensive clinical studies in patients suffering from non-small cell lung cancer, breast cancer, multiple myeloma and other haematological malignancies. Data regarding the anti-cancer effect of Cla on Colorectal Cancer (CRC) are still lacking. This article shares data on the efficacy of Cla in two xenograft models of CRC. Our results show that Cla treatment reduces tumour growth and increases the overall survival in CRC mouse xenograft models. Moreover, the Western blot analysis of autophagic and apoptotic markers suggests that the anti-tumour effects of Cla are related to a modulation of both cellular processes. The data suggest that it will worth consider Cla as treatment option for CRC patients.
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http://dx.doi.org/10.1016/j.dib.2019.104406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727004PMC
October 2019

The ion channels and transporters gene expression profile indicates a shift in excitability and metabolisms during malignant progression of Follicular Lymphoma.

Sci Rep 2019 06 13;9(1):8586. Epub 2019 Jun 13.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

The definition of the gene expression profile of genes encoding Ion Channels and Transporters (ICT-GEP) represents a novel and attracting aspect in cancer. We determined the ICT-GEP of Follicular Lymphoma (FL), and compared it with that of the more aggressive Diffuse Large B Cell Lymphoma (DLBCL). cDNA microarray data were collected both from patients enrolled for this study, and from public datasets. In FL the ICT-GEP indicated the overexpression of both the K channel encoding gene KCNN4, and SLC2A1, which encodes the Glut1 glucose transporter. SLC2A1 turned out to represent the hub of a functional network, connecting channels and transporters in FL. Relapsed FL patients were characterised by 38 differentially expressed ICT genes, among which ATP9A, SLC2A1 and KCNN4 were under-expressed, indicating a down-regulation of both excitability and glycolysis. A completely different profile of K channel encoding genes emerged in DLBCL accompanied by the over-expression of the fatty acid transporter-encoding gene SLC27A1 as well as of the metabolism regulator NCoR1. This indicates a change in excitability and a shift towards an oxidative metabolism in DLBCL. Overall, the ICT-GEP may contribute to identifying novel lymphoma biomarkers related to excitability and metabolic pathways, with particular relevance for drug resistant, relapsed FL.
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http://dx.doi.org/10.1038/s41598-019-44661-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565741PMC
June 2019

Replacement of the Thiosugar of Auranofin with Iodide Enhances the Anticancer Potency in a Mouse Model of Ovarian Cancer.

ACS Med Chem Lett 2019 Apr 7;10(4):656-660. Epub 2019 Feb 7.

Laboratory of Metals in Medicine (MetMed), Department of Chemistry "U. Schiff", University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.

In recent years, a few successful attempts were made to repurpose the clinically approved antiarthritic gold drug, Auranofin (), as an anticancer agent. The present study shows that the iodido(triethylphosphine)gold(I) complex, ( hereafter)-an analogue where the thiosugar ligand is simply replaced by one iodide ligand-manifests a solution chemistry resembling that of and exerts similar cytotoxic and proapoptotic effects on A2780 human ovarian cancer cells . However, when evaluated in a preclinical orthotopic model of ovarian cancer, produces a far superior anticancer action than inducing a nearly complete tumor remission. The highly promising performances here documented for warrant its further evaluation as a drug candidate for ovarian cancer treatment.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466815PMC
April 2019

Pilot investigation of the mutation profile of PIK3CA/PTEN genes (PI3K pathway) in grade 3 endometrial cancer.

Oncol Rep 2019 Mar 18;41(3):1560-1574. Epub 2018 Dec 18.

Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and Gynecology, University of Florence, I‑50134 Florence, Italy.

Endometrial cancer (EC) comprises a biological and clinical heterogeneous group of tumors. Several genetic alterations are involved in the development and progression of EC, and may be used for targeted therapy, particularly in patients with advanced‑stage EC. In the present study, a combined procedure was developed based on polymerase chain reaction (PCR)‑high resolution melting analysis (HRMA) and Sanger sequencing for the evaluation of somatic mutations in selected phosphoinositide 3‑kinase (PI3K) catalytic subunit α (PIK3CA; exons 1, 9 and 21) and phosphatase and tensin homolog (PTEN; exons 5, 6, 7 and 8) exons. This combined procedure has the specificity and sensitivity of the two techniques, and overcomes their limitations. A pilot study was performed on 18 selected homogenous EC samples, of grade 3 endometrioid subtype (G3 EEC). First, the feasibility of the combined procedure was investigated to properly identify the presence of somatic mutations on PIK3CA and PTEN, the variations identified were analyzed using Catalogue of Somatic Mutations in Cancer, PolyPhen‑2 and Mutation Taster software, and the frequency of mutations/variations was determined in the selected samples. The evaluation of mutational load revealed that the majority of the G3 EEC samples exhibited PIK3CA mutations (39%) and PTEN mutations (67%), and the majority of the samples (83%) had mutations in at least one of the two genes, and 33% had mutations in the two genes. The results of the present pilot study suggested that the cost‑effective combined PCR‑HRMA and Sanger sequencing procedure may be suitable for identification of PTEN and PIK3CA mutations in G3 EEC and that their frequency was consistent in G3 EEC, indicating that the PI3K pathway serves a pivotal function that may have potential for defining targeted therapy for the treatment of G3 EEC.
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http://dx.doi.org/10.3892/or.2018.6939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365709PMC
March 2019

Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias.

Oncol Rep 2019 Jan 18;41(1):312-324. Epub 2018 Oct 18.

Department of Experimental and Clinical Medicine, University of Florence, I‑50134 Florence, Italy.

Notable advances in treatment have been made and increases in the cure rates of pediatric leukemia have been achieved. However, the majority of children with relapsed disease are not expected to survive, with chemotherapy resistance acting as the principal cause of treatment failure. Interaction between leukemic cells and the bone marrow microenvironment is the primary cause of relapse. It was identified that a multi‑protein membrane complex, formed by potassium voltage‑gated channel subfamily H member 2 (hERG1) channels, the β1 integrin subunit and the stromal cell‑derived factor 12 (CXCL12) receptor, C‑X‑C chemokine receptor type 4 (CXCR4), exerts a role in mesenchymal stromal cell (MSC)‑mediated chemoresistance in pediatric leukemias. hERG1 blockade was able to overcome chemoresistance in vitro and in vivo. As an alternative strategy to overcome chemoresistance, the present study evaluated the effects of novel tools targeting the CXCR4/CXCL12 axis. The analysis of CXCL12 structural dynamics was used for the selection of a peptide (4‑1‑17) and a small molecule (8673), which interact with a transient hot spot, identified by a dynamic drug design approach. The present findings indicated that peptide 4‑1‑17 and small molecule 8673 inhibited leukemia cell proliferation and induced a pro‑apoptotic effect, which was not reduced by the presence of MSCs. The combined treatment with 4‑1‑17 and 8673 had a stronger pro‑apoptotic effect, particularly on cells cultured on MSCs in normoxic and hypoxic conditions, and was able to overcome MSC‑induced resistance to cytarabine. Overall, the targeting of CXCL12 and the ensuing inhibition of the CXCR4/CXCL12 axis may be proposed as an alternative strategy to overcome chemoresistance in leukemia.
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http://dx.doi.org/10.3892/or.2018.6808DOI Listing
January 2019

Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Immunohistochemical Score Associated with Poor Prognosis in Endometrial Cancer Patients.

Biomed Res Int 2018 2;2018:1618056. Epub 2018 Apr 2.

Department of Biomedical Clinical and Experimental Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.

The aim of this study was to develop a scoring system of the immunohistochemical (IHC) expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCG-R) in endometrial cancer (EC) patients. Nonconsecutive hysterectomy specimens containing EC collected from April 2013 to October 2015 were selected. Hematoxylin-eosin stained sections from each case were reviewed and representative sections from each tumor were selected. IHC staining was performed for the detection of LHCG-R. The percentage of stained cells and the staining intensity were assessed in order to develop an immunohistochemical score. Moreover, we examined the correlation of the score with grading and lymphovascular space invasion (LVSI). There was a statistically significant positive correlation between grading and IHC scoring ( = 0.01) and a statistically significant positive correlation between LVSI and IHC score ( < 0.01). In conclusion, we suggest that the immunohistochemical score presented here could be used as a marker of bad prognosis of EC patients. Nevertheless, further studies are needed in order to validate it. The study was registered in the Careggi Hospital public trials registry with the following number: 2013/0011391.
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http://dx.doi.org/10.1155/2018/1618056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902075PMC
October 2018

Engineering l-asparaginase for spontaneous formation of calcium phosphate bioinspired microreactors.

Phys Chem Chem Phys 2018 May;20(18):12719-12726

Magnetic Resonance Center (CERM), University of Florence and Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.

Active bioinspired materials are appealing biotechnological targets, and their study is gaining momentum. These materials, which comprise of an inorganic matrix and one or more biomolecules, are extremely variable and therefore may result difficult to characterize in their intimate structure. In this work we have prepared a hydroxyapatite-l-asparaginase composite, with the perspective of using it in acute leukemia treatment. We demonstrate that the use of electron microscopy and powder X-ray diffraction, combined with the atomic-resolution information coming from solid-state NMR, allows us to understand the topology of the material and how the different components interplay to obtain an active composite.
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http://dx.doi.org/10.1039/c8cp00419fDOI Listing
May 2018

Severe hypoxia selects hematopoietic progenitors with stem cell potential from primary Myelodysplastic syndrome bone marrow cell cultures.

Oncotarget 2018 Feb 24;9(12):10561-10571. Epub 2018 Jan 24.

MDS UNIT, Hematology, AOU-Careggi University Hospital, Department of Experimental and Clinical Medicine, Università degli Studi di Firenze, Florence, Italy.

Myelodysplastic Syndromes (MDS) are clonal neoplasms where stem/progenitor cells endowed with self-renewal and capable of perpetuating the disease have been demonstrated. It is known that oxygen tension plays a key role in driving normal hematopoiesis and that hematopoietic stem cells are maintained in hypoxic areas of the bone marrow (BM). Hypoxia could also regulate leukemic/dysplastic hematopoiesis. We evaluated the stem cell potential of MDS cells derived from the BM of 39 MDS patients and selected under severe hypoxia. MDS cells rescued from hypoxia-incubated cultures were subjected to stem and progenitor cell assays as well as to hematopoietic reconstitution assay in NOD-SCID mice. Incubation in severe hypoxia of cells explanted from MDS patients selected a cell subset endowed with stem cell potential, as determined . This occurred only from the BM of patients classified as IPSS low/INT-1 risk. Transplantation into NOD-SCID mice confirmed using an model that severe hypoxia selects a cell subset endowed with stem cell potential from bone marrow mononuclear cells (BMMC). derived from patients belonging to the IPSS low/int-1 risk group. Data here reported show that cells endowed with stem cell potential and capable of adapting to hypoxia and escaping hypoxia-induced apoptosis exist within MDS cell populations.
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http://dx.doi.org/10.18632/oncotarget.24302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828219PMC
February 2018

The combined activation of K3.1 and inhibition of K11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells.

Br J Cancer 2018 01 21;118(2):200-212. Epub 2017 Nov 21.

Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy.

Background: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K channel modulators on colorectal cancer (CRC) cells.

Methods: The functional expression of Ca-activated (K3.1, also known as KCNN4) and voltage-dependent (K11.1, also known as KCNH2 or hERG1) K channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K channel modulators were tested in vitro for their action on K currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance.

Results: Cisplatin-resistant CRC cells expressed higher levels of K3.1 and K11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, K3.1 activators (SKA-31) and K11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when K3.1 activation and K11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate K3.1 and inhibit K11.1. Cisplatin uptake into resistant cells depended on K3.1 channel activity, as it was potentiated by K3.1 activators. K11.1 blockade led to increased K3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a K3.1 activator and a K11.1 inhibitor also overcame Cisplatin resistance in vivo.

Conclusions: As Riluzole, an activator of K3.1 and inhibitor of K11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC.
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http://dx.doi.org/10.1038/bjc.2017.392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785745PMC
January 2018

Circulating Endothelial Progenitor Cells in Type 1 Diabetic Patients: Relation with Patients' Age and Disease Duration.

Front Endocrinol (Lausanne) 2017 23;8:278. Epub 2017 Oct 23.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Objectives: Circulating endothelial progenitor cells (cEPCs) have been reported to be dysfunctional in diabetes mellitus (DM) patients, accounting for the vascular damage and the ensuing high risk for cardiovascular disease (CVD) characteristic of this disease. The aim of the present study was to evaluate the number of circulating cEPCs in type 1 DM (T1DM) patients, without clinical vascular damage, of different ages and with different disease duration.

Methods: An observational, clinical-based prospective study was performed on T1DM patients enrolled in two clinical centers. cEPCs were determined by flow cytometry, determining the number of CD34/CD133/VEGFR2-positive cells within peripheral blood mononuclear cells (PBMCs).

Results: The number of cEPCs was lower in adult T1DM patients, whilst higher in childhood/young patients, compared to controls of the same age range. When patients were grouped into two age groups (≥ or <20 years) (and categorized on the basis of the duration of the disease), the number of cEPCs in young (<20 years) patients was higher compared with older subjects, regardless of disease duration. A subset of patients with very high cEPCs was identified in the <20 years group.

Conclusion: There is an association between the number of cEPCs and patients' age: childhood/young T1DM patients have significantly higher levels of cEPCs, respect to adult T1DM patients. Such difference is maintained also when the disease lasts for more than 10 years. The very high levels of cEPCs, identified in a subset of childhood/young patients, might protect vessels against endothelial dysfunction and damage. Such protection would be less operative in older subjects, endowed with lower cEPC numbers, in which complications are known to develop more easily.
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http://dx.doi.org/10.3389/fendo.2017.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660067PMC
October 2017

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression.

Sci Signal 2017 Apr 4;10(473). Epub 2017 Apr 4.

Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.

Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K flux through the human ether-à-go-go-related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the β integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the β integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with β integrins as did closed channels, current flow through hERG1 channels was necessary to activate the integrin-dependent phosphorylation of Tyr in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K flow, whereas metastasis of breast cancer cells was reduced when the hERG1/β integrin interaction was disrupted. We conclude that the interaction of β integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression.
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http://dx.doi.org/10.1126/scisignal.aaf3236DOI Listing
April 2017

Potent in vitro antiproliferative properties for a triplatinum cluster toward triple negative breast cancer cells.

J Inorg Biochem 2016 10 27;163:318-322. Epub 2016 Jun 27.

Laboratory of Metals in Medicine, Department of Chemistry, University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy. Electronic address:

The trinuclear platinum cluster [Pt(μ-PBu)(CO)]CFSO (I) was designed featuring the presence of a nearly equilateral platinum triangle bridged by three di-tert-butylphosphide ligands; in addition, each platinum center bears a terminal carbonyl ligand. This triplatinum cluster was initially developed in view of applications in the field of cluster-containing innovative materials. Yet, due to the large success of platinum complexes in cancer treatment, we also decided to explore its cytotoxic and anticancer properties. Accordingly, the solubility profile of this compound in several solvents was preliminarily investigated, revealing a conspicuous solubility in DMSO and DMSO/buffer mixtures; this makes the biological testing of I amenable. UV-Vis measurements showed that the triplatinum cluster is stable for several hours under a variety of conditions, within aqueous environments. No measurable reactivity was observed for I toward two typical model proteins, i.e. lysozyme and cytochrome c. On the contrary, a significant reactivity was evidenced when reacting I with small sulfur-containing ligands. In particular, a pronounced reactivity with reduced glutathione and cysteine emerged from ESI-MS experiments, proving complete formation of I-GSH and I-Cys derivatives, with the loss of a single carbonyl ligand. Starting from these encouraging results, the cytotoxic potential of I was assayed in vitro against a panel of representative cancer cell lines, and potent cytotoxic properties were disclosed. Of particular interest is the finding that the triplatinum species manifests potent antiproliferative properties toward Triple Negative Breast Cancer Cells, often refractory to most anticancer drugs. Owing to the reported encouraging results, a more extensive biological and pharmacological evaluation of this Pt cluster is now warranted to better elucidate its mode of action.
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http://dx.doi.org/10.1016/j.jinorgbio.2016.06.024DOI Listing
October 2016

Antiproliferative properties and biomolecular interactions of three Pd(II) and Pt(II) complexes.

J Inorg Biochem 2016 12 30;165:1-6. Epub 2016 Sep 30.

Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia. Electronic address:

Three Pd(II) and Pt(II) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands i.e. [Pd(DMEAIm)Cl] (1) (DMEAIm, 2-(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)ethan-1-dimethylamine), [Pd(DACH(Im)Cl] (2) (DACH(Im, N,N'-(cyclohexane-1,2-diyl)bis(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)) and [Pt(DMEAIm)Cl] (3), are evaluated here as potential cytotoxic and anticancer agents. An acceptable solution behaviour was found for the three study compounds in terms of solubility and stability. Notably, the three metal complexes demonstrated moderate to high cytotoxic properties in selected cancer cell lines (liquid and solid tumor). To gain deeper mechanistic insight, the reactivity of the study complexes with model DNA oligos and protein molecules was investigated through spectrometric and spectroscopic methods; in both cases adduct formation was clearly documented by ESI-MS measurements. The binding of these metal complexes to calf thymus DNA (CT-DNA) was further examined by absorption (UV-Vis) and emission spectral studies (Ethidium bromide displacement studies, EtBr). Overall, the studied complexes 1-3 exhibited a remarkable DNA binding ability that might be linked to the observed cytotoxic effects. Interestingly our results revealed that DNA binding, as well as anticancer activity of 1-3 follows the order 2>3>1. The implications of these findings are discussed.
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http://dx.doi.org/10.1016/j.jinorgbio.2016.09.016DOI Listing
December 2016

LH/hCG-Receptor Expression May Have a Negative Prognostic Value in Low-Risk Endometrial Cancer.

Front Oncol 2016 25;6:190. Epub 2016 Aug 25.

Department of Biomedical, Clinical and Experimental Sciences, University of Florence , Florence , Italy.

Introduction: A 51 year-old woman was diagnosed with endometrial cancer (EC) and underwent surgical staging. Pathological evaluation showed a 2 cm × 1 cm G2 endometrioid EC with a 30% myometrial deep invasion (FIGO Stage 1A). The patient was classified as low risk of recurrence, and no adjuvant treatment was offered. Six months after surgery, the patient developed an early vescico-vaginal recurrence, and chemotherapy treatment was started. Few months later, a subsequent involvement of vaginal wall, ileum, and omentum was detected, and the patient underwent second surgery.

Background: LH/hCG-receptor (LH/hCG-R) expression has been previously reported to be associated with an invasive phenotype in EC cells. Moreover, in a preclinical mouse model of EC behaves as a prometastatic molecular device.

Discussion: We analyzed the expression level of LH/hCG-R in cancer specimens collected during surgeries. Molecular and immunohistochemical analyses showed a strong expression of both mRNA and protein for LH/hCG-R in all specimens.

Conclusion: LH/hCG-R expression may be assessed together with other clinicopathological parameters in order to better predict the risk of recurrence in low-risk EC patients. Further clinical trials are warranted in order to validate LH/hCG-R as biomarker in EC.
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http://dx.doi.org/10.3389/fonc.2016.00190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996991PMC
September 2016

New gold carbene complexes as candidate anticancer agents.

Biometals 2016 10 6;29(5):905-11. Epub 2016 Aug 6.

(MetMed) Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Italy.

Three structurally related gold(I) carbene complexes with bulky hydrophobic ligands i.e. 1-3 were investigated in solution for further consideration as candidate anticancer agents. Cytotoxic assays were subsequently conducted on bone marrow-derived preosteoclast cell line of human origin (FLG 29.1) and human colon cancer cells (HCT-116). A far greater cytotoxic activity was measured for compound 1 against HCT-116 cells compared to 2 and 3; conversely, all compounds were highly and similarly active against FLG 29.1 cells. Results obtained for the reaction of complexes 1 and 2 with RNase A documented the occurrence of a weak interaction with this model protein and the formation of a tiny amount of the corresponding adduct. Moreover, a certain reactivity of the complex 2 was also detected toward GSH. The general implications of the obtained results are discussed.
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http://dx.doi.org/10.1007/s10534-016-9962-0DOI Listing
October 2016

Cisplatin and its dibromido analogue: a comparison of chemical and biological profiles.

Biometals 2016 06 16;29(3):535-42. Epub 2016 Apr 16.

Laboratory of Metals in Medicine (MetMed), Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Italy.

The dibromido analogue of cisplatin, cis-PtBr2(NH3)2 (cisPtBr2 hereafter), has been prepared and characterised. Its solution behaviour in standard phosphate buffer, at pH 7.4, was investigated spectrophotometrically and found to reproduce quite closely that of cisplatin; indeed, progressive sequential release of the two halide ligands typically occurs as in the case of cisplatin, with a roughly similar kinetics. Afterward, patterns of reactivity toward model proteins and standard ctDNA were explored and the nature of the resulting interactions elucidated. The antiproliferative properties were then evaluated in four representative cancer cell lines, namely A549 (human lung cancer), HCT116 (human colon cancer), IGROV-1 (human ovarian cancer) and FLG 29.1 (human acute myeloid leukaemia). Cytotoxic properties in line with those of cisplatin were highlighted. From these studies an overall chemical and biological profile emerges for cisPtBr2 closely matching that of cisplatin; the few slight, but meaningful differences that were underscored might be advantageously exploited for clinical application.
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http://dx.doi.org/10.1007/s10534-016-9934-4DOI Listing
June 2016

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug.

Sci Rep 2015 Dec 2;5:17736. Epub 2015 Dec 2.

University of Siena, Department of Medical Biotechnologies, Siena, 53100, Italy.

Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity.
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http://dx.doi.org/10.1038/srep17736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667195PMC
December 2015

cis-Pt I2(NH3)2: a reappraisal.

Dalton Trans 2015 Sep;44(33):14896-905

MetMed, Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.

The investigation of cis-PtI2(NH3)2, the diiodido analogue of cisplatin (cisPtI2 hereafter), has been unjustly overlooked so far mainly because of old claims of pharmacological inactivity. Some recent - but still fragmentary - findings prompted us to reconsider more systematically the chemical and biological profile of cisPtI2 in comparison with cisplatin. Its solution behaviour, interactions with DNA and cytotoxic properties versus selected cancer cell lines were thus extensively analysed through a variety of biophysical and computational methods. Notably, we found that cisPtI2 is highly cytotoxic in vitro toward a few solid tumour cell lines and that its DNA platination pattern closely reproduces that of cisplatin; cisPtI2 is also shown to completely overcome resistance to cisplatin in a platinum resistant cancer cell line. The differences in the biological actions of these two Pt complexes are most likely related to slight but meaningful differences in their solution behaviour and reactivity. Overall, a very encouraging and unexpected pharmacological profile emerges for cisPtI2 with relevant implications both in terms of mechanistic knowledge and of prospective clinical application. An ab initio DFT study is also included to support the interpretation of the solution behaviour of cisPtI2 under physiological and slightly acidic pH conditions.
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http://dx.doi.org/10.1039/c5dt01196eDOI Listing
September 2015

Design, synthesis and characterisation of new chimeric ruthenium(II)-gold(I) complexes as improved cytotoxic agents.

Dalton Trans 2015 Jun 21;44(24):11067-76. Epub 2015 May 21.

Laboratory of Metals in Medicine, Department of Chemistry, University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.

Two heterobimetallic complexes, i.e. [RuCl2(p-cymene)(μ-dppm)AuC] (1) and [RuCl2(p-cymene)(μ-dppm)Au(S-thiazoline)] (3), based on known cytotoxic [Ru(p-cymene)Cl2(PR3)] and [AuX(PR3)] (X = Cl, SR) molecular scaffolds, with the diphosphane linker 1,1-bis(diphenylphosphino)methane, dppm, were conveniently prepared and characterised. Remarkably, the new compounds manifested a more favourable in vitro pharmacological profile toward cancer cells than individual ruthenium and gold species being either more cytotoxic or more selective. The interactions of the studied compounds with (pBR322) DNA and their inhibitory effects on cathepsin B were also assessed. In addition, their reactivity toward suitable models of protein targets was explored and clear evidence gained for disruption of the bimetallic motif and for protein binding of monometallic fragments. Overall, the data reported here strongly support the concept of multifunctional heterometallic compounds as "improved" candidate agents for cancer treatment. The mechanistic and pharmacological implications of the present findings are discussed.
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http://dx.doi.org/10.1039/c5dt01614bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464950PMC
June 2015

New pyrimido-indole compound CD-160130 preferentially inhibits the KV11.1B isoform and produces antileukemic effects without cardiotoxicity.

Mol Pharmacol 2015 Feb 19;87(2):183-96. Epub 2014 Nov 19.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.G., S.P., A.A.); Department of Chemistry "Ugo Schiff," University of Florence, Florence, Italy (M.M., A.P.); DI.V.A.L. Toscana srl, Sesto Fiorentino, Italy (M.D.A., M.M.); Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom (R.C., R.K., J.S.M.); BlackSwan Pharma GmbH, Leipzig, Germany (W.T., K.M.); Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy (G.B.); and Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy (A.B.)

KV11.1 (hERG1) channels are often overexpressed in human cancers. In leukemias, KV11.1 regulates pro-survival signals that promote resistance to chemotherapy, raising the possibility that inhibitors of KV11.1 could be therapeutically beneficial. However, because of the role of KV11.1 in cardiac repolarization, blocking these channels may cause cardiac arrhythmias. We show that CD-160130, a novel pyrimido-indole compound, blocks KV11.1 channels with a higher efficacy for the KV11.1 isoform B, in which the IC50 (1.8 μM) was approximately 10-fold lower than observed in KV11.1 isoform A. At this concentration, CD-160130 also had minor effects on Kir2.1, KV 1.3, Kv1.5, and KCa3.1. In vitro, CD-160130 induced leukemia cell apoptosis, and could overcome bone marrow mesenchymal stromal cell (MSC)-induced chemoresistance. This effect was caused by interference with the survival signaling pathways triggered by MSCs. In vivo, CD-160130 produced an antileukemic activity, stronger than that caused by cytarabine. Consistent with its atypical target specificity, CD-160130 did not bind to the main binding site of the arrhythmogenic KV11.1 blockers (the Phe656 pore residue). Importantly, in guinea pigs CD-160130 produced neither alteration of the cardiac action potential shape in dissociated cardiomyocytes nor any lengthening of the QT interval in vivo. Moreover, CD-160130 had no myelotoxicity on human bone marrow-derived cells. Therefore, CD-160130 is a promising first-in-class compound to attempt oncologic therapy without cardiotoxicity, based on targeting KV11.1. Because leukemia and cardiac cells tend to express different ratios of the A and B KV11.1 isoforms, the pharmacological properties of CD-160130 may depend, at least in part, on isoform specificity.
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http://dx.doi.org/10.1124/mol.114.094920DOI Listing
February 2015