Antagonistic anticancer effect of paclitaxel and digoxin combination

Pereira, Duane G.; Rendeiro, Mariana Manzano; Cortes, Vanessa Faria; Barbosa, Leandro A.; Quintas, Luis Eduardo M.

doi:10.1002/jcb.28583

Cited by 10 publications

(5 citation statements)

References 33 publications

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“…Several authors have demonstrated that chemotherapeutic drugs control tumor tissue growth by reducing cell viability[ 28 , 65 , 66 ] and activating distinct signaling transduction pathways that involve PKC[ 67 ], MEK[ 68 ], ERK1/2[ 69 ], Ras[ 70 ], p38MAPK[ 71 ] and NF-κB[ 72 ]. In particular, PX exerts its effects via the activation of different kinase signaling pathways depending on the cell type analyzed[ 73 - 75 ].…”

Section: Discussionmentioning

confidence: 99%

Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells

Español¹,

Sanchez²,

Salem³

et al. 2022

WJCO

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BACKGROUND Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients’ treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients. AIM To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells. METHODS Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers’ blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP “binding cassette” G2 drug transporter (ABCG2) expression and its modulation by the different treatments with Western blot. The effect of the treatments on apoptosis induction was determined by flow cytometry using annexin-V and 7AAD markers. RESULTS Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells. CONCLUSION Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.

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Section: Discussionmentioning

confidence: 99%

Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells

Español¹,

Sanchez²,

Salem³

et al. 2022

WJCO

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“…Digitoxin also displayed potent cytotoxicity against HeLa cervical cancer cells with an IC50 value of 28 nM after 48 h of exposure [182]. Following a 48 h exposure to digoxin, the viability of both human lung (A549) and cervical cancer (HeLa) cell lines were adversely affected in a concentrationdependent manner, resulting in IC50 values of 31 nM for A549 cells and 151 nM for HeLa cells [183]. The anti-EBV and broad-spectrum anticancer properties, as well as specific anti-cervical cancer activities observed in these cardiac glycosides, make ZINC000095909247 an interesting candidate to probe further.…”

Section: Structural Similarity Search Of the Potential Candidatesmentioning

confidence: 99%

Structure-Based Discovery of Potential HPV E6 and EBNA1 Inhibitors: Implications for Cervical Cancer Treatment

Broni,

Ashley,

Velazquez

et al. 2024

Computation

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Cervical cancer is the fourth most diagnosed cancer and the fourth leading cause of cancer death in women globally. Its onset and progression have been attributed to high-risk human papillomavirus (HPV) types, especially 16 and 18, while the Epstein–Barr virus (EBV) is believed to also significantly contribute to cervical cancer growth. The E6 protein associated with high-risk HPV strains, such as HPV16 and HPV18, is known for its role in promoting cervical cancer and other anogenital cancers. E6 proteins contribute to the malignant transformation of infected cells by targeting and degrading tumor suppressor proteins, especially p53. On the other hand, EBV nuclear antigen 1 (EBNA1) plays a crucial role in the maintenance and replication of the EBV genome in infected cells. EBNA1 is believed to increase HPV E6 and E7 levels, as well as c-MYC, and BIRC5 cellular genes in the HeLa cell line, implying that HPV/EBV co-infection accelerates cervical cancer onset and growth. Thus, the E6 and EBNA1 antigens of HPV and EBV, respectively, are attractive targets for cervical cancer immunotherapy. This study, therefore, virtually screened for potential drug candidates with good binding affinity to all three oncoviral proteins, HPV16 E6, HPV18 E6, and EBNA1. The compounds were further subjected to ADMET profiling, biological activity predictions, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations. A total of six compounds comprising ZINC000013380012, ZINC000070454124, ZINC000014588133, ZINC000085568136, ZINC000095909247, and ZINC000085597263 demonstrated very strong affinity (≤−60 kJ/mol) to the three oncoviral proteins (EBNA1, HPV16 E6, and HPV18 E6) after being subjected to docking, MD, and MM/PBSA. These compounds demonstrated relatively stronger binding than the controls used, inhibitors of EBNA1 (VK-1727) and HPV E6 (baicalein and gossypetin). Biological activity predictions also corroborated their antineoplastic, p53-enhancing, Pin1 inhibitory, and JAK2 inhibitory activities. Further experimental testing is required to validate the ability of the shortlisted compounds to silence the insidious effects of HPV E6 and EBNA1 proteins in cervical cancers.

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“…Due to its relative simplicity, predictability, precision, and accuracy, assessing particular blood biomarkers of cardiac damage has been proposed as an appealing, legitimate, and new technique to identify and monitor cardiotoxicity in patients treated with chemotherapy [45]. Troponin, B-type natriuretic peptide (BNP), and NT-proBNP are the three main serum markers [46]. The "guardian of the genome" serum P53 shields cells from recurring cancer.…”

Section: Monitoring and Diagnosis Of Cardiotoxicitymentioning

confidence: 99%

Chemotherapy-induced cardiotoxicity: a new perspective on the role of Digoxin, ATG7 activators, Resveratrol, and herbal drugs

Al-Hussaniy

Alburghaif

Alkhafaje³

et al. 2023

JMedLife

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Cancer is a major public health problem, and chemotherapy plays a significant role in the management of neoplastic diseases. However, chemotherapy-induced cardiotoxicity is a serious side effect secondary to cardiac damage caused by antineoplastic's direct and indirect toxicity. Currently, there are no reliable and approved methods for preventing or treating chemotherapy-induced cardiotoxicity. Understanding the mechanisms of chemotherapy-induced cardiotoxicity may be vital to improving survival. The independent risk factors for developing cardiotoxicity must be considered to prevent myocardial damage without decreasing the therapeutic efficacy of cancer treatment. This systematic review aimed to identify and analyze the evidence on chemotherapy-induced cardiotoxicity, associated risk factors, and methods to decrease or prevent it. We conducted a comprehensive search on PubMed, Google Scholar, and Directory of Open Access Journals (DOAJ) using the following keywords: "doxorubicin cardiotoxicity", "anthracycline cardiotoxicity", "chemotherapy", "digoxin decrease cardiotoxicity", "ATG7 activators", retrieving 59 articles fulfilling the inclusion criteria. Therapeutic schemes can be changed by choosing prolonged infusion application over boluses. In addition, some agents like Dexrazoxane can reduce chemotherapy-induced cardiotoxicity in high-risk groups. Recent research found that Digoxin, ATG7 activators, Resveratrol, and other medical substances or herbal compounds have a comparable effect on Dexrazoxane in anthracycline-induced cardiotoxicity.

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Antagonistic anticancer effect of paclitaxel and digoxin combination

Cited by 10 publications

References 33 publications

Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells

Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells

Structure-Based Discovery of Potential HPV E6 and EBNA1 Inhibitors: Implications for Cervical Cancer Treatment

Chemotherapy-induced cardiotoxicity: a new perspective on the role of Digoxin, ATG7 activators, Resveratrol, and herbal drugs

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