New bufadienolides extracted from Rhinella marina inhibit Na,K-ATPase and induce apoptosis by activating caspases 3 and 9 in human breast and ovarian cancer cells

Garcia, Israel José Pereira; Oliveira, Gisele Capanema de; Valadares, Jéssica Martins de Moura; Banfi, Felipe Finger; Andrade, Silmara Nunes; Freitas, Túlio Resende; Filho, Evaldo dos Santos Monção; Santos, Hérica de Lima; Júnior, Gerardo Magela Vieira; Chaves, Mariana Helena; Rodrigues, Domingos de Jesus; Sanchez, Bruno A. M.; Varotti, Fernando P.; Barbosa, Leandro A.

doi:10.1016/j.steroids.2019.108490

Cited by 17 publications

(18 citation statements)

References 56 publications

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“…Discovery and development of new drugs, in particular anticancer drugs, from natural products, has been the focus of much research. The α-pyrone is one of the most abundant scaffolds in naturally occurring molecules, in which many are cytotoxic agents with anticancer potentials, such as bufadienolides, gibepyrones, higginsianins, and pironetin [36][37][38][39][40]. The (+)-brevipolide H, which belongs to the naturally occurring 5,6-dihydro-α-pyrone derivatives, displayed anti-proliferative and apoptotic activities against CRPCs in the present work.…”

Section: Discussionmentioning

confidence: 53%

The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis

et al. 2020

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Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca2+, two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.

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Section: Discussionmentioning

confidence: 53%

The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis

et al. 2020

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“…They can also be found endogenously in mammals, including humans, in salt-sensitive hypertensive states such as congestive heart-failure or preeclampsia [42][43][44][45]. Bufadienolides possess a steroid structure with a δ-lactone ring at carbon C17 of ring D and they are synthetized from cholesterol as precursor through the mevalonate-independent pathways [28,46]. In mammals, they are produced in the adrenal cortex through a pathway independent of cholesterol side-chain cleavage [47].…”

Section: Discussionmentioning

confidence: 99%

“…Rhinella marina-better known as the cane toad-is predominantly present in Central and Latin America and some parts of Australia. These two toad species were selected because they have already shown strong anticancer effects on hematological, solid, sensitive and/or resistant human tumor cell lines [14,[26][27][28]. Their compound fingerprints have already been widely studied and so has their anticancer effects on different cancer types.…”

Section: Introductionmentioning

confidence: 99%

Toad Venom Antiproliferative Activities on Metastatic Melanoma: Bio-Guided Fractionation and Screening of the Compounds of Two Different Venoms

Soumoy

Wells

Najem

et al. 2020

Biology

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Melanoma is the most common cancer in young adults, with a constantly increasing incidence. Metastatic melanoma is a very aggressive cancer with a 5-year survival rate of about 22−25%. This is, in most cases, due to a lack of therapies which are effective on the long term. Hence, it is crucial to find new therapeutic agents to increase patient survival. Toad venoms are a rich source of potentially pharmaceutically active compounds and studies have highlighted their possible effect on cancer cells. We focused on the venoms of two different toad species: Bufo bufo and Rhinella marina. We screened the venom crude extracts, the fractions from crude extracts and isolated biomolecules by studying their antiproliferative properties on melanoma cells aiming to determine the compound or the combination of compounds with the highest antiproliferative effect. Our results indicated strong antiproliferative capacities of toad venoms on melanoma cells. We found that these effects were mainly due to bufadienolides that are cardiotonic steroids potentially acting on the Na+/K+ ATPase pump which is overexpressed in melanoma. Finally, our results indicated that bufalin alone was the most interesting compound among the isolated bufadienolides because it had the highest antiproliferative activity on melanoma cells.

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“…In PE, when CS are elevated, Na/K-ATPase is depressed and Fli1 is low this results in the occurrence of a phenotype associated with a significantly lower incidence of breast cancer [59,60] (Figure 2). At the same time in breast cancer patients (Figure 2) CS and Na/K-ATPase are regular [61][62][63][64][65] and Fli1 is high [66][67][68]; i.e., as if patients with PE administered an anti-CS antibody. Could it be true for the other types of cancer?…”

Section: Ros C-srcmentioning

confidence: 94%

Preeclampsia: Cardiotonic Steroids, Fibrosis, Fli1 and Hint to Carcinogenesis

Agalakova

Kolodkin

Adair

et al. 2021

IJMS

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Despite prophylaxis and attempts to select a therapy, the frequency of preeclampsia does not decrease and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present a new theory of the etiology and pathogenesis of preeclampsia that is based on the interaction of Na/K-ATPase and its endogenous ligands including marinobufagenin. The signaling pathway of marinobufagenin involves an inhibition of transcriptional factor Fli1, a negative regulator of collagen synthesis, followed by the deposition of collagen in the vascular tissues and altered vascular functions. Moreover, in vitro and in vivo neutralization of marinobufagenin is associated with the restoration of Fli1. The inverse relationship between marinobufagenin and Fli1 opens new possibilities in the treatment of cancer; as Fli1 is a proto-oncogene, a hypothesis on the suppression of Fli1 by cardiotonic steroids as a potential anti-tumor therapeutic strategy is discussed as well. We propose a novel therapy of preeclampsia that is based on immunoneutralization of the marinobufagenin by monoclonal antibodies, which is capable of impairing marinobufagenin-Na/K-ATPase interactions.

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New bufadienolides extracted from Rhinella marina inhibit Na,K-ATPase and induce apoptosis by activating caspases 3 and 9 in human breast and ovarian cancer cells

Cited by 17 publications

References 56 publications

The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis

The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis

Toad Venom Antiproliferative Activities on Metastatic Melanoma: Bio-Guided Fractionation and Screening of the Compounds of Two Different Venoms

Preeclampsia: Cardiotonic Steroids, Fibrosis, Fli1 and Hint to Carcinogenesis

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