scholarly journals Tuning the Cytotoxicity of Bis-Phosphino-Amines Ruthenium(II) Para-Cymene Complexes for Clinical Development in Breast Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1559
Author(s):  
Elena Domínguez-Jurado ◽  
Francisco J. Cimas ◽  
José Antonio Castro-Osma ◽  
Alberto Juan ◽  
Agustín Lara-Sánchez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acquired Resistance ◽  
In Vitro Cytotoxicity ◽  
Clinical Development ◽  
Rational Drug Design ◽  
Preclinical Development ◽  
Cancer Subtypes ◽  
Ruthenium Compounds

Despite some limitations such as long-term side effects or the potential presence of intrinsic or acquired resistance, platinum compounds are key therapeutic components for the treatment of several solid tumors. To overcome these limitations, maintaining the same efficacy, organometallic ruthenium(II) compounds have been proposed as a viable alternative to platinum agents as they have a more favorable toxicity profile and represent an ideal template for both, high-throughput and rational drug design. To support the preclinical development of bis-phoshino-amine ruthenium compounds in the treatment of breast cancer, we carried out chemical modifications in the structure of these derivatives with the aim of designing less toxic and more efficient therapeutic agents. We report new bis-phoshino-amine ligands and the synthesis of their ruthenium counterparts. The novel ligands and compounds were fully characterized, water stability analyzed, and their in vitro cytotoxicity against a panel of tumor cell lines representative of different breast cancer subtypes was evaluated. The mechanism of action of the lead compound of the series was explored. In vivo toxicity was also assessed. The results obtained in this article might pave the way for the clinical development of these compounds in breast cancer therapy.

SN38 polymeric nanoparticles: In vitro cytotoxicity and in vivo antitumor efficacy in xenograft balb/c model with breast cancer versus irinotecan

2014 ◽  
Vol 471 (1-2) ◽  
pp. 485-497 ◽  
Author(s):  
Nima Sepehri ◽  
Hasti Rouhani ◽  
Faranak Tavassolian ◽  
Hamed Montazeri ◽  
Mohammad Reza Khoshayand ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Polymeric Nanoparticles ◽  
In Vitro Cytotoxicity ◽  
Antitumor Efficacy

scholarly journals Breast Cancer Chemotherapeutic Options: A General Overview on the Preclinical Validation of a Multi-Target Ruthenium(III) Complex Lodged in Nucleolipid Nanosystems

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1412
Author(s):  
Maria Grazia Ferraro ◽  
Marialuisa Piccolo ◽  
Gabriella Misso ◽  
Francesco Maione ◽  
Daniela Montesarchio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Preclinical Development ◽  
Cell Death Pathways ◽  
Complex Information ◽  
Ru Complexes ◽  
Therapeutic Alternatives

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium-based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple-negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced next-generation metallotherapeutics, with NAMI-A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well-known NAMI-A complex, information on non-nanostructured Ru-based anticancer agents have been included in a precise manner.

scholarly journals Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Giada Zurlo ◽  
Xijuan Liu ◽  
Mamoru Takada ◽  
Cheng Fan ◽  
Jeremy M. Simon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Protein Level ◽  
Triple Negative ◽  
Normal Breast ◽  
Cancer Subtypes ◽  
Adenylosuccinate Lyase ◽  
Non Coding Rna

AbstractProtein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

scholarly journals Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

2019 ◽  
Vol 116 (9) ◽  
pp. 3863-3872 ◽  
Author(s):  
Sandra Blasco-Benito ◽  
Estefanía Moreno ◽  
Marta Seijo-Vila ◽  
Isabel Tundidor ◽  
Clara Andradas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cannabinoid Receptor ◽  
Acquired Resistance ◽  
Diagnostic Tools ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2–CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2–HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.

scholarly journals Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors

2020 ◽  
Vol 12 (534) ◽  
pp. eaaw8275 ◽  
Author(s):  
Johanna M. Schafer ◽  
Brian D. Lehmann ◽  
Paula I. Gonzalez-Ericsson ◽  
Clayton B. Marshall ◽  
J. Scott Beeler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Clinical Investigation ◽  
Mek Inhibitors ◽  
Cancer Subtypes ◽  
Bet Inhibitors

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not respond to endocrine therapy or human epidermal growth factor receptor 2 (HER2)–targeted therapies. Individuals with TNBC experience higher rates of relapse and shorter overall survival compared to patients with receptor-positive breast cancer subtypes. Preclinical discoveries are needed to identify, develop, and advance new drug targets to improve outcomes for patients with TNBC. Here, we report that MYCN, an oncogene typically overexpressed in tumors of the nervous system or with neuroendocrine features, is heterogeneously expressed within a substantial fraction of primary and recurrent TNBC and is expressed in an even higher fraction of TNBCs that do not display a pathological complete response after neoadjuvant chemotherapy. We performed high-throughput chemical screens on TNBC cell lines with varying amounts of MYCN expression and determined that cells with higher expression of MYCN were more sensitive to bromodomain and extraterminal motif (BET) inhibitors. Combined BET and MEK inhibition resulted in a synergistic decrease in viability, both in vitro and in vivo, using cell lines and patient-derived xenograft (PDX) models. Our preclinical data provide a rationale to advance a combination of BET and MEK inhibitors to clinical investigation for patients with advanced MYCN-expressing TNBC.

scholarly journals Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

2020 ◽  
Author(s):  
Xiao Tan ◽  
Zhongqiang Zhang ◽  
Ping Liu ◽  
Hongliang Yao ◽  
jingshan tong
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Acquired Resistance ◽  
Proteasome Inhibitors ◽  
Resistant Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Akt Inhibitor

Abstract Background: PIK3CA mutations are common genomic alterations in estrogen receptor (ER)-positive breast cancers, currently, the development of selective PI3Kα (phosphatidylinositol 3-kinase α) inhibitors is ongoing. The mechanisms contributing to the anticancer activity of alpelisib in PIK3CA-mutant breast cancer cells and the mechanism of acquired resistance to alpelisib remain elusive. Methods: Drug-sensitive cell lines were exposed to alpelisib to establish alpelisib-resistant cell lines. Western blotting was used to assess changes in protein expression. Apoptosis was evaluated by flow cytometry. In vivo with mouse xenograft models and in vitro colony formation and MTS and assay were carried out to determine the growth inhibitory effects of the tested drugs. Protein half-lives were examined and proteasome inhibitors were used to estimate protein degradation. Gene knockdown was carried out using shRNA or siRNA. Results: In the present study, we report the potent induction of apoptosis by alpelisib in PIK3CA-mutant breast cancer cell lines. AKT phosphorylation suppression, AKT/Foxo3a-dependent Bim induction, and AKT/GSK-3β-dependent Mcl-1 degradation were observed. Apoptosis induced by alpelisib was attenuated by Mcl-1 (4A) overexpression or Bim suppression. Furthermore, alpelisib could not modulate Mcl-1 or Bim levels in cell lines that were resistant to alpelisib. AKT inhibitor and alpelisib combination restored the sensitivity of alpelisib-resistant cells to growth inhibition and apoptosis in vitro and in vivo. Conclusions: Therefore, modulation of Mcl-1 degradation and AKT-dependent Bim induction are crucial for mediating the resistance and sensitivity of PIK3CA-mutant breast tumor cells to alpelisib, thus making it a productive strategy for overcoming acquired resistance to alpelisib.

scholarly journals Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

2021 ◽  
Author(s):  
Laura E de Vries ◽  
Patrick AM Jansen ◽  
Catalina Barcelo ◽  
Justin Munro ◽  
Julie MJ Verhoef ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Clinical Development ◽  
Target Validation ◽  
Humanized Mouse ◽  
Preclinical Development ◽  
Humanized Mouse Model ◽  
Pharmacodynamic Modelling ◽  
Biochemical Studies

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound showed exceptional in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocked P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identified ACS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. MMV693183 was well adsorbed after oral administration in mice, rats and dogs. Pharmacokinetic-pharmacodynamic modelling predicted that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. In conclusion, the ACS-targeting compound MMV693183 represents a promising addition to the portfolio of antimalarials in (pre)clinical development with a novel mode of action for the treatment of malaria and blocking transmission.

scholarly journals Targeted Chinese Medicine Delivery by A New Family of Biodegradable Pseudo-Protein Nanoparticles for Treating Triple-Negative Breast Cancer: In Vitro and In Vivo Study

2021 ◽  
Vol 10 ◽  
Author(s):  
Hiu Yee Kwan ◽  
Qinghua Xu ◽  
Ruihong Gong ◽  
Zhaoxiang Bian ◽  
Chih-Chang Chu
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Targeted Delivery ◽  
Triple Negative ◽  
Underlying Mechanism ◽  
Gambogic Acid ◽  
Cancer Subtypes ◽  
New Family

Triple negative breast cancer (TNBC) has the worst overall survival among all breast cancer subtypes; 80% of TNBC harbors TP53 mutation. Gambogic acid (GA) is an herbal compound isolated from the dry brownish gamboge resin of Garcinia hanburyi. A new family of biodegradable polymer, the folate (FA)-conjugated arginine-based poly(ester urea urethane)s nanoparticles (FA-Arg-PEUU NP), was developed as nano-carrier for GA. Its anti-TNBC effects and the underlying mechanism of action were examined. The average diameters of FA-Arg-PEUU NP and GA-loaded FA-Arg-PEUU NP (NP-GA) in water are around 165 and 220nm, respectively. Rhodamine-tagged FA-Arg-PEUU NP shows that the conjugation of FA onto Arg-PEUU NPs facilitates the internalization of FA-Arg-PEUU-NP into TNBC. Compared to free-GA at the same GA concentrations, NP-GA exhibits higher cytotoxicity in both TP53-mutated and non-TP53 expressed TNBC cells by increasing intrinsic and extrinsic apoptosis. In HCC1806-bearing xenograft mouse model, the targeted delivery of GA by the FA-Arg-PEUU-NP nano-carriers to the tumor sites results in a more potent anti-TNBC effect and lower toxicity towards normal tissues and organs when compared to free GA. Furthermore, NP-GA also reduces the tumor-associated macrophage (TAM) M1/M2 ratio, suggesting that the use of Arg-based nanoparticles as carriers for GA not only makes the surface of the nanoparticles positively charged, but also confers on to the nanoparticles an ability to modulate TAM polarization. Our data clearly demonstrate that NP-GA exhibits potent anti-TNBC effects with reduced off-target toxicity, which represents novel alternative targeted therapeutics for TNBC treatment.

scholarly journals Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2773 ◽  
Author(s):  
Coralie Poulard ◽  
Julien Jacquemetton ◽  
Olivier Trédan ◽  
Pascale A. Cohen ◽  
Julie Vendrell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
In Vitro Models ◽  
Proximity Ligation Assay ◽  
Breast Cancers ◽  
Cancer Management ◽  
Tamoxifen Resistant

Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα–Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.

scholarly journals Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Eswara Murali Satyavarapu ◽  
Prasun Kumar Sinha ◽  
Chitra Mandal
Keyword(s):  
Breast Cancer ◽  
Chronic Toxicity ◽  
Hematological Parameters ◽  
Clinical Signs ◽  
Murraya Koenigii ◽  
Preclinical Development ◽  
Dapi Staining ◽  
Wide Range

Murraya koenigii is well documented in the Indian ancient medical text “Charaka Samhita.” The carbazole alkaloid “mahanine” from this plant exhibited anticancer activity against several cancers. Here, we have taken a comprehensive study to standardize the method for the preparation of a mahanine-enriched fraction (MEF) with the highest yield and defined markers. Our optimized method produced MEF having the highest amount of mahanine, a major marker, with excellent in vitro antiproliferative activity against ovarian and breast cancer cells as evidenced by decreased cell viability by MTT assay. Moreover, it exhibited condensed and fragmented nuclei by DAPI staining and increased annexin V-/PI-stained cells after MEF treatment, indicating apoptosis. It also exhibited good efficacy in ovarian and breast cancer syngeneic mice models, with an ED50 of 300 mg/kg body weight (BW). MEF is stable up to 40°C for ≥3 months. Its biological activity remains unchanged at a wide range of pH (1-10) for up to ~3 hours, indicating a safe oral route of administration. Additionally, the comparative pharmacokinetics of MEF and mahanine in rats showed a 31% higher bioavailability of mahanine in MEF-fed rats compared to rats fed with mahanine alone. Furthermore, mice fed with MEF at 5000 mg/kg BW single dose, 300-1500 mg/kg BW/day for 14 days, and 300 mg/kg BW/day for 28, 90, and 180 days for subacute, subchronic, chronic studies, respectively, did not show any significant clinical signs of toxicity, behavioral changes, mortality, organ weights, serum biochemistry, and hematological parameters indicating no/minimum toxicity for up to 180 days. To the best of our knowledge, this is the first report showing the pH/temperature stability and chronic toxicity studies of MEF along with in vivo efficacy against breast cancer. Taken together, our study will enhance the commercial value of this highly potential medicinal plant and will be helpful as a reference material for its clinical development.

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