[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer <i>in vivo</i>

Martín, Ángel G.; Fuzer, Angelina Maria; Becceneri, Amanda Blanque; Silva, James Almada da; Tomasin, Rebeka; Denoyer, Delphine; Kim, Soohyun; McIntyre, Katherine; Pearson, Helen; Yeo, Belinda; Nagpal, Aadya; Ling, Xiawei; Selistre-de-Araújo, Heloísa Sobreiro; Vieira, Paulo C.; Cominetti, Márcia Regina; Pouliot, Normand

doi:10.18632/oncotarget.20139

Cited by 68 publications

(41 citation statements)

References 37 publications

(43 reference statements)

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“…Gingerol is a major phenolic compound present in the rhizomes of ginger (Z. officinale Roscoe). In a syngenic mouse model of spontaneous breast cancer metastasis, gingerol (5 mg/ kg) treatment induced caspase-3 activation and inhibited the orthotopic tumor growth as well as metastasis of mouse brainmetastatic 4T1Br4 mammary tumor cells to multiple organs such as lung, bone and brain (Martin et al, 2017). Likewise, Joo and colleagues (Joo et al, 2016) reported inhibition of lungmetastatic, MDA-MB-231 human breast cancer cell proliferation, and invasion by [10]-gingerol through suppression of Akt, p38MAPK, and epidermal growth factor receptor.…”

Section: Phytochemicals In Pre-clinical Trialsmentioning

confidence: 99%

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

et al. 2020

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Cancer is a severe health problem that continues to be a leading cause of death worldwide. Increasing knowledge of the molecular mechanisms underlying cancer progression has led to the development of a vast number of anticancer drugs. However, the use of chemically synthesized drugs has not significantly improved the overall survival rate over the past few decades. As a result, new strategies and novel chemoprevention agents are needed to complement current cancer therapies to improve efficiency. Naturally occurring compounds from plants known as phytochemicals, serve as vital resources for novel drugs and are also sources for cancer therapy. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, and podophyllotoxin analogs. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancer. The specific mechanisms include increasing antioxidant status, carcinogen inactivation, inhibiting proliferation, induction of cell cycle arrest and apoptosis; and regulation of the immune system. The primary objective of this review is to describe what we know to date of the active compounds in the natural products, along with their pharmacologic action and molecular or specific targets. Recent trends and gaps in phytochemical based anticancer drug discovery are also explored. The authors wish to expand the phytochemical research area not only for their scientific soundness but also for their potential druggability. Hence, the emphasis is given to information about anticancer phytochemicals which are evaluated at preclinical and clinical level.

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Section: Phytochemicals In Pre-clinical Trialsmentioning

confidence: 99%

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

et al. 2020

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“…To verify whether the complex (2) is able to arrest cell cycle, propidium iodide (PI) staining was performed, as described earlier [27]. MDA-MB-231 and MCF-10A cells were seeded (5 × 10 5 /1000 μL) in appropriate culture medium into 6 cm Petri dishes and maintained at 37°C in a humidified incubator with 5% CO 2 for 24 h. After, cells were treated or not (control) with different concentrations of the complex (2) (0.5, 1 and 2 μM) for 24 h and maintained under the same conditions described above.…”

Section: Cell Cyclementioning

confidence: 99%

The trans -[Ru(PPh 3 ) 2 ( N , N -dimethyl- N ′-thiophenylthioureato-k 2 O,S)(bipy)]PF 6 complex has pro-apoptotic effects on triple negative breast cancer cells and presents low toxicity in vivo

Becceneri

Popolin

Plutı́n

et al. 2018

Journal of Inorganic Biochemistry

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Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epidermal growth factor receptor 2 (HER-2) gene. Despite all the advances in cancer treatments, the development of new anticancer drugs for TNBC tumors is still a challenge. There is an increasing interest in new agents to be used in cancer treatment. Ruthenium is a metal that has unique characteristics and important in vivo and in vitro results achieved for cancer treatment. Thus, in this work, with the aim to develop anticancer drugs, three new ruthenium complexes containing acylthiourea ligands have been synthesized and characterized: trans-[Ru(PPh)(N,N-dibutyl-N'-benzoylthioureato-kO,S)(2,2'-bipyridine (bipy))]PF(1), trans-[Ru(PPh)(N,N-dimethyl-N'-thiophenylthioureato-kO,S)(bipy)]PF(2) and trans-[Ru(PPh)(N,N-dimethyl-N'-benzoylthioureato-kO,S)(bipy)]PF(3). Then, the cytotoxicity of these three new ruthenium complexes was investigated in TNBC MDA-MB-231 and in non-tumor MCF-10A cells. Complex (2) was the most selective complex and was chosen for further studies to verify its effects on cell morphology, adhesion, migration, invasion, induction of apoptosis and DNA damage in vitro, as well as its toxicity and capacity of causing DNA damage in vivo. Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells at lower concentrations compared to non-tumor MCF-10A cells, suggesting an effective action for this complex on tumor cells. Finally, complex (2) did not induce toxicity or caused DNA damage in vivo when low doses were administered to mice.

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“…The organs were harvested, photographed, fixed in 10% buffered formalin for 24 h and processed for histology. Tumour growth and spontaneous metastasis assays were completed as described previously [34,42]. For these assays, fluorescent mCherry-tagged TBCP-1 cells (1 × 10 6 /20 μl PBS) were inoculated into the fourth mammary fat pad and tumour growth measured thrice weekly with electronic callipers.…”

Section: Tumour Growth Metastasis Assays and Neratinib Therapymentioning

confidence: 99%

“…The incidence of mice with brain metastases at endpoint was determined by ex vivo fluorescence imaging using a Maestro™ In-Vivo Imaging System (CRi) and, where indicated, further confirmed by histology and cytokeratin staining (see below). Relative metastatic burden in the lungs, femurs and spine of the control and treatment groups was quantitated by genomic qPCR detection of the mCherry marker gene present in tumour cells only, relative to the vimentin gene present in tumour and host cells, as described previously [34,37,42].…”

Section: Tumour Growth Metastasis Assays and Neratinib Therapymentioning

confidence: 99%

Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis

et al. 2019

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Background: Human epidermal growth factor receptor-2 (HER2)-targeted therapies prolong survival in HER2positive breast cancer patients. Benefit stems primarily from improved control of systemic disease, but up to 50% of patients progress to incurable brain metastases due to acquired resistance and/or limited permeability of inhibitors across the blood-brain barrier. Neratinib, a potent irreversible pan-tyrosine kinase inhibitor, prolongs disease-free survival in the extended adjuvant setting, and several trials evaluating its efficacy alone or combination with other inhibitors in early and advanced HER2-positive breast cancer patients are ongoing. However, its efficacy as a firstline therapy against HER2-positive breast cancer brain metastasis has not been fully explored, in part due to the lack of relevant pre-clinical models that faithfully recapitulate this disease. Here, we describe the development and characterisation of a novel syngeneic model of spontaneous HER2-positive breast cancer brain metastasis (TBCP-1) and its use to evaluate the efficacy and mechanism of action of neratinib. Methods: TBCP-1 cells were derived from a spontaneous BALB/C mouse mammary tumour and characterised for hormone receptors and HER2 expression by flow cytometry, immunoblotting and immunohistochemistry. Neratinib was evaluated in vitro and in vivo in the metastatic and neoadjuvant setting. Its mechanism of action was examined by transcriptomic profiling, function inhibition assays and immunoblotting. Results: TBCP-1 cells naturally express high levels of HER2 but lack expression of hormone receptors. TBCP-1 tumours maintain a HER2-positive phenotype in vivo and give rise to a high incidence of spontaneous and experimental metastases in the brain and other organs. Cell proliferation/viability in vitro is inhibited by neratinib and by other HER2 inhibitors, but not by anti-oestrogens, indicating phenotypic and functional similarities to human HER2-positive breast cancer. Mechanistically, neratinib promotes a non-apoptotic form of cell death termed ferroptosis. Importantly, metastasis assays demonstrate that neratinib potently inhibits tumour growth and metastasis, including to the brain, and prolongs survival, particularly when used as a neoadjuvant therapy.

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[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo

Cited by 68 publications

References 37 publications

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

The trans -[Ru(PPh 3 ) 2 ( N , N -dimethyl- N ′-thiophenylthioureato-k 2 O,S)(bipy)]PF 6 complex has pro-apoptotic effects on triple negative breast cancer cells and presents low toxicity in vivo

Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis

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