Iodide Analogs of Arsenoplatins—Potential Drug Candidates for Triple Negative Breast Cancers

Patients with triple negative breast cancers (TNBCs)—highly aggressive tumors that do not express estrogen, progesterone, and human epidermal growth factor 2 receptors—have limited treatment options. Fewer than 30% of women with metastatic TNBC survive five years after their diagnosis, with a mortality rate within three months after a recurrence of 75%. Although TNBCs show a higher response to platinum therapy compared to other breast cancers, drug resistance remains a major obstacle; thus, platinum drugs with novel mechanisms are urgently needed. Arsenoplatins (APs) represent a novel class of anticancer agents designed to contain the pharmacophores of the two FDA approved drugs cisplatin and arsenic trioxide (As2O3) as one molecular entity. Here, we present the syntheses, crystal structures, DFT calculations, and antiproliferative activity of iodide analogs of AP-1 and AP-2, i.e., AP-5 and AP-4, respectively. Antiproliferative studies in TNBC cell lines reveal that all AP family members are more potent than cisplatin and As2O3 alone. DFT calculations demonstrate there is a low energy barrier for hydrolysis of the platinum-halide bonds in arsenoplatins, possibly contributing to their higher cytotoxicities compared to cisplatin.

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Prognostic Evaluation of Epidermal Growth Factor Receptor (EGFR) Genotype and Phenotype Parameters in Triple-negative Breast Cancers

Cancer Genomics & Proteomics ◽

10.21873/cgp.20030 ◽

2017 ◽

Vol 14 (3) ◽

pp. 181-195 ◽

Cited By ~ 13

Author(s):

SOFIA LEVVA ◽

VASSILIKI KOTOULA ◽

IOANNIS KOSTOPOULOS ◽

KYRIAKI MANOUSOU ◽

CHRISTOS PAPADIMITRIOU ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Triple Negative ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Prognostic Evaluation ◽

Epidermal Growth

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The “Yin and Yang” of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers

Cancers ◽

10.3390/cancers10100346 ◽

2018 ◽

Vol 10 (10) ◽

pp. 346 ◽

Cited By ~ 28

Author(s):

Elizabeth Varghese ◽

Samson Samuel ◽

Mariam Abotaleb ◽

Sohaila Cheema ◽

Ravinder Mamtani ◽

...

Keyword(s):

Side Effects ◽

Anticancer Agents ◽

Triple Negative ◽

Natural Compounds ◽

Chemotherapeutic Agents ◽

Mitogen Activated Protein Kinase ◽

Breast Cancers ◽

Plant Metabolites ◽

Mesenchymal Transition ◽

Targeted Interventions

Among the different types of breast cancers, triple-negative breast cancers (TNBCs) are highly aggressive, do not respond to conventional hormonal/human epidermal growth factor receptor 2 (HER2)-targeted interventions due to the lack of the respective receptor targets, have chances of early recurrence, metastasize, tend to be more invasive in nature, and develop drug resistance. The global burden of TNBCs is increasing regardless of the number of cytotoxic drugs being introduced into the market each year as they have only moderate efficacy and/or unforeseen side effects. Therefore, the demand for more efficient therapeutic interventions, with reduced side effects, for the treatment of TNBCs is rising. While some plant metabolites/derivatives actually induce the risk of cancers, many plant-derived active principles have gained attention as efficient anticancer agents against TNBCs, with fewer adverse side effects. Here we discuss the possible oncogenic molecular pathways in TNBCs and how the purified plant-derived natural compounds specifically target and modulate the genes and/or proteins involved in these aberrant pathways to exhibit their anticancer potential. We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/β-catenin, Notch, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects.

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HER-2-Amplified Breast Cancer

10.2310/cgso.16010 ◽

2018 ◽

Author(s):

Zahraa Al-Hilli ◽

Judy C Boughey

Keyword(s):

Breast Cancer ◽

Treatment Options ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Breast Cancers ◽

Aggressive Disease ◽

Node Positive Disease ◽

Her 2 ◽

Epidermal Growth ◽

Positive Breast Cancer

Amplification of the human epidermal growth factor receptor–2 (HER-2) gene is found in approximately 15 to 30% of breast cancers. Historically, HER-2 overexpression has been associated with aggressive disease and a poor prognosis. However, the use of targeted anti-HER2 therapy has revolutionized the treatment of HER-2-positive disease, and the use of the monoclonal antibody trastuzumab in combination with chemotherapy is now standard of care for tumors greater than 1 cm in size and in node-positive disease. More recently, the value of dual-agent anti-HER-2 therapy has been demonstrated in large clinical trials. This review provides an overview of HER-2-positive breast cancer, its molecular basis, methods of identification, and treatment options and strategies. This review contains 2 figures and 70 references Key words: anti-HER-2 therapy, breast cancer, HER-2-positive breast cancer, HER-2 resistance, lapatinib, neoadjuvant chemotherapy, pertuzumab, small HER-2-positive breast cancer, trastuzumab

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Practical Approach to Triple-Negative Breast Cancer

Journal of Oncology Practice ◽

10.1200/jop.2017.022632 ◽

2017 ◽

Vol 13 (5) ◽

pp. 293-300 ◽

Cited By ~ 24

Author(s):

Vijayakrishna K. Gadi ◽

Nancy E. Davidson

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Hormone Receptors ◽

Triple Negative ◽

Early Stage ◽

Management Strategies ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Epidermal Growth ◽

Proven Method

Triple negative is a term applied to breast cancers that do not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase. At present, the only proven method for systemic management of triple-negative breast cancer for both early-stage and metastatic settings is cytotoxic chemotherapy. Here, we provide a comprehensive review of management strategies that are best supported by available data. We also review recent advances most likely to affect treatment of triple-negative breast cancer in the coming years with particular emphasis on targeted agents, biologics, and immunotherapy.

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Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma

Investigational New Drugs ◽

10.1007/s10637-020-01037-7 ◽

2020 ◽

Author(s):

Mohamed E. M. Saeed ◽

Onat Kadioglu ◽

Henry Johannes Greten ◽

Adem Yildirim ◽

Katharina Mayr ◽

...

Keyword(s):

Rna Sequencing ◽

Treatment Options ◽

Drug Repurposing ◽

Sequencing Data ◽

Survival Times ◽

Chemical Library ◽

Ki 67 ◽

Drug Candidates ◽

Egfr Expression ◽

Approved Drugs

SummaryBackground Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.

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Triple Negative Breast Cancer: A Brief Review of its Characteristics and Treatment Options

Journal of Pharmacy Practice ◽

10.1177/0897190012442062 ◽

2012 ◽

Vol 25 (3) ◽

pp. 319-323 ◽

Cited By ~ 57

Author(s):

Carrie L. Griffiths ◽

Jacqueline L. Olin

Keyword(s):

Breast Cancer ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Growth Factor Receptor ◽

Her 2 ◽

Epidermal Growth

Triple negative breast cancer (TNBC), an aggressive variant of breast cancer, is characterized by lack of expression of the estrogen (ER) and progesterone receptors (PRs) and the human epidermal growth factor receptor (HER-2) that are commonly observed in other breast cancer subtypes. The TNBC subtype primarily occurs in younger women of African American or Hispanic descent and tumors tend to be high grade and initially responsive to chemotherapy. However, TNBC is characteristically aggressive with high recurrence, metastatic, and mortality rates. Treatment options are limited since the hormonal receptor and HER-2 antagonists typically used for other breast cancers are ineffective. As such, the mainstay of treatment of TNBC is traditional systemic cytotoxic chemotherapy. Potential future therapies for TNBC include targeted molecular strategies including poly (adenosine diphosphate ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents. Further research aimed at identifying unique genetic characteristics of TNBC may allow development of other targeted molecular chemotherapy treatment options.

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Triple-Negative Breast Cancer

10.2310/cgso.16011 ◽

2019 ◽

Author(s):

Diane M. Radford ◽

Jame Abraham ◽

Stephen R. Grobmyer

Keyword(s):

Breast Cancer ◽

African American Women ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Cancer Breast ◽

Gene Testing ◽

Visceral Metastases ◽

Epidermal Growth

Triple-negative breast cancers (TNBCs), negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, account for 15 to 20% of all female breast cancers. TNBC is heterogeneous based on gene expression microarray, and identification of TNBC subtypes and their behavior has the potential to enable more targeted, neoadjuvant, and adjuvant interventions. TNBCs usually are higher grade (Nottingham score 3) and are more common in younger, Hispanic, and African American women. They are more aggressive, have an increased likelihood of distant disease and mortality, are larger at presentation, and are more likely to be associated with lymph node metastases. Patients with TNBC are at a higher risk for visceral metastases early in the course of the disease. Genetic risk evaluation is recommended for patients with TNBC diagnosed at or before 60 years of age. Surgical management may be influenced by gene testing results. Standard adjuvant chemotherapy is anthracycline or taxane based. This review contains 5 figures, 8 tables, and 51 references. Key Words: adjuvant, BRCA, chemotherapy, hormone receptor negative, neoadjuvant, genetics, triple-negative breast cancer, breast neoplasm.

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A paclitaxel and microRNA-124 coloaded stepped cleavable nanosystem against triple negative breast cancer

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00800-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Chuanrong Chen ◽

Ming Shen ◽

Hongze Liao ◽

Qianqian Guo ◽

Hao Fu ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Disulfide Bonds ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Treatment Options ◽

Breast Cancers ◽

Mesenchymal Transition ◽

Tumour Metastasis ◽

Microrna 124

Abstract Background Triple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis. Therefore, studies aiming to explore new therapeutic strategies for advanced TNBC are urgently needed. According to recent studies, microRNA-124 (miR124) not only inhibits tumour growth but also increases the sensitivity of TNBC to paclitaxel (PTX), suggesting that a platform combining PTX and miR124 may be an advanced solution for TNBC. Results Herein, we constructed a stepped cleavable calcium phosphate composite lipid nanosystem (CaP/LNS) to codeliver PTX and miR124 (PTX/miR124-NP). PTX/miR124-NP exhibited superior tumor microenvironment responsive ability, in which the surface PEG layer was shed in the mildly acidic environment of tumor tissues and exposed oligomeric hyaluronic acid (o-HA) facilitated the cellular uptake of CaP/LNS by targeting the CD44 receptor on the surface of tumor cells. Inside tumour cells, o-HA detached from CaP/LNS due to the reduction of disulfide bonds by glutathione (GSH) and inhibited tumour metastasis. Then, PTX and miR124 were sequentially released from CaP/LNS and exerted synergistic antitumour effects by reversing the Epithelial-Mesenchymal Transition (EMT) process in MDA-MB-231 cells. Moreover, PTX/miR124-NP showed significant antitumour efficiency and excellent safety in mice bearing MDA-MB-231 tumours. Conclusion Based on these results, the codelivery of PTX and miR124 by the CaP/LNS nanosystem might be a promising therapeutic strategy for TNBC.

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Current and emerging treatment options in triple-negative breast cancer

Oncology Reviews ◽

10.4081/oncol.2010.5 ◽

2011 ◽

Vol 4 (1) ◽

pp. 5

Author(s):

Omer Dizdar ◽

Kadri Altundag

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

Treatment Options ◽

Growth Factor Receptor ◽

Immunohistochemical Analysis ◽

Endocrine Treatment ◽

Breast Cancers ◽

Chemotherapy Drugs

Triple-negative breast cancer is defined by the lack of estrogen receptor, progesterone receptor and HER2 expression with immunohistochemical analysis. Triplenegative breast cancers are poorly differentiated, characterized by high histological grade and occur at a younger age. Treatment options are limited as these tumors are naturally resistant to existing targeted therapies, i.e., endocrine treatment and trastuzumab. An improved understanding of the biology of TNBC has led to evaluation of DNA-damaging chemotherapy drugs and targeted agents, including poly (ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, etc., in the treatment of TNBC. This review focuses on outlining the current and emerging treatment options in patients with triple-negative breast cancer.

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Optical Redox Imaging Differentiates Triple-Negative Breast Cancer Subtypes

Advances in Experimental Medicine and Biology - Oxygen Transport to Tissue XLII ◽

10.1007/978-3-030-48238-1_40 ◽

2021 ◽

pp. 253-258

Author(s):

Jinxia Jiang ◽

Min Feng ◽

Annemarie Jacob ◽

Lin Z. Li ◽

He N. Xu

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Response Patterns ◽

Breast Cancers ◽

Cancer Subtypes ◽

Mitochondrial Inhibitors ◽

Tnbc Cell

AbstractTriple-negative breast cancer (TNBC) is a highly diverse group of cancers with limited treatment options, responsible for about 15% of all breast cancers. TNBC cells differ from each other in many ways such as gene expression, metabolic activity, tumorigenicity, and invasiveness. Recently, many research and clinical efforts have focused on metabolically targeted therapy for TNBC. Metabolic characterization of TNBC cell lines can facilitate the assessment of therapeutic effects and assist in metabolic drug development. Herein, we used optical redox imaging (ORI) techniques to characterize TNBC subtypes metabolically. We found that various TNBC cell lines had differing redox statuses (levels of reduced nicotinamide adenine dinucleotide (NADH), oxidized flavin adenine dinucleotide (FAD), and the redox ratio (FAD/(NADH+FAD)). We then metabolically perturbed the cells with mitochondrial inhibitors and an uncoupler and performed ORI accordingly. As expected, we observed that these TNBC cell lines had similar response patterns to the metabolic perturbations. However, they exhibited differing redox plasticity. These results suggest that subtypes of TNBC cells are different metabolically and that ORI can serve as a sensitive technique for the metabolic profiling of TNBC cells.

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