Digoxin Enhances the Anticancer Effect on Non-Small Cell Lung Cancer While Reducing the Cardiotoxicity of Adriamycin

Wang, Yingying; Ma, Qian; Zhang, Shaolu; Liu, Hongyan; Zhao, Baofeng; Du, Bo; Wang, Wei; Lin, Peng; Zhang, Zhe; Zhong, Yuxu

doi:10.3389/fphar.2020.00186

Cited by 51 publications

(35 citation statements)

References 37 publications

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“…After treatment with BKM120 or/and rucaparib for 12/24 h, U251 and U87MG cells were collected and subjected to alkaline comet assay for detection of both SSBs and DSBs as we described previously 42 . The cells (1 × 10 5 /ml) were combined with molten LMAgarose at a ratio of 1:10 (v/v), and 50 µl of cell suspension was immediately added onto comet slides.…”

Section: Methodsmentioning

confidence: 99%

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

Zhang

Peng

et al. 2021

Cell Death Dis

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PARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of “synthetic lethality”. However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker γ-H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.

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Section: Methodsmentioning

confidence: 99%

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

Zhang

Peng

et al. 2021

Cell Death Dis

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“…However, there are few reports on this aspect. Besides, digoxin also showed good antitumor activity in multiple cancer types [26][27][28]. Therefore, we used digoxin as a positive control and found that both THB and it have a strong inhibitory effect on lung cancer, but THB appeared to show better tumor suppressive effect in NSCLC mouse model without signi cant difference.…”

Section: Discussionmentioning

confidence: 99%

Thevebioside, the Active Ingredient of Traditional Chinese Medicine, Inhibits SRC3 Mediated Signaling by Ubiquitination to Induce NSCLC Cells Apoptosis

Yao

Zhang

et al. 2020

Preprint

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Background:The high incidence and mortality of lung cancer has been a widespread concern in the world, among which non-small cell lung cancer (NSCLC)accounts for more than 85% of lung cancer, and its 5-year prognosis is pretty poor. Accumulating studies have shown that traditional Chinese medicine (TCM) and its active ingredients have shown good anti-tumor activity. Based on the results of our previous high-throughput screening, it was the first time to find that Thevebioside (THB, an active ingredient from TCM) is sensitive to NSCLC cells, and then we will still the first to reveal the underling mechanism of its tumor suppressive activity.Methods: In this study, MTT and colony formation assay were used to detect cell growth. Annexin V/ propidium iodide, Hoechst 33342 were applied to test the process of cellular apoptosis or cell cycle arrest which determined by flow cytometry in NSCLC (A549 and H460) cells. qRT-PCR and Western blot was utilized to value the level of expression of SRC&(SRC1-3) and apoptosis related proteins. The ubiquitination degradation of SRC3 was through proteasome dependent pathway were examined by the usage of CHX and MG132 and the co-immunoprecipitation assay. The anticancer activity of THB, Neritaloside，Odoroside H and digoxin in vivo were monitored in nude mice by subcutaneous inoculation or intrapulmonary injection of A549 cells and then administrated these agents (2 mg/ kg or 4mg/kg) by intraperitoneal injection three times a week for 30 days. Tumor growth was monitored by a luciferase living imaging system. Body weight of mice and tumor volume were measured weekly. The survival carve was recorded. Pathological histology of liver, kidney and heart were detected by H&E staining, and its functions were tested by ELISA. Results：THB effectively inhibits the outgrowth of NSCLC cells (A549 and H460) by inducing cellular apoptosis. SRC-3 was significantly down-regulated after THB treatment dependent on ubiquitin-proteasome-mediated degradation, which subsequently inhibited the AKT signaling pathway to promte apoptosis. Animal study supported in vitro results, showing THB had a good suppressive effect on tumor growth. Besides, it also indicated that THB without overt cytotoxic effect on liver, kidney and heart.Conclusion：THB , as an active extract from TCM，exerted inhibitory effect on tumor growth of NSCLC by down-regulating the expression of SCR-3 rely on the ubiquitin-proteasome degradation pathway, thereby inhibiting the AKT signaling to induce cellular apoptosis , with minimal toxicity.

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“…Interestingly, the antitumor effect of these anti-proliferative agents can be evaluated alongside any cardiac toxicity secondary to cancer therapy. In one study, zebrafish and mice xenograft models were injected with A549 cells and then used to assess co-treatment of doxorubicin with digoxin, an inotropic agent used in heart failure [ 65 ]. Co-treatment with digoxin enhanced the antitumor effect of doxorubicin in both organisms and reduced cardiotoxicity caused by doxorubicin in mice, as quantified by the heart size and cardiomyocyte size postmortem.…”

Section: Zebrafish As a Model To Study Cancer Biologymentioning

confidence: 99%

Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity

Lane

Asnani

2021

JCDD

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Purpose of review: Both traditional and novel cancer therapies can cause cardiovascular toxicity in patients. In vivo models integrating both cardiovascular and cancer phenotypes allow for the study of on- and off-target mechanisms of toxicity arising from these agents. The zebrafish is the optimal whole organism model to screen for cardiotoxicity in a high throughput manner, while simultaneously assessing the role of cardiotoxicity pathways on the cancer therapy’s antitumor effect. Here we highlight established zebrafish models of human cardiovascular disease and cancer, the unique advantages of zebrafish to study mechanisms of cancer therapy-associated cardiovascular toxicity, and finally, important limitations to consider when using the zebrafish to study toxicity. Recent findings: Cancer therapy-associated cardiovascular toxicities range from cardiomyopathy with traditional agents to arrhythmias and thrombotic complications associated with newer targeted therapies. The zebrafish can be used to identify novel therapeutic strategies that selectively protect the heart from cancer therapy without affecting antitumor activity. Advances in genome editing technology have enabled the creation of several transgenic zebrafish lines valuable to the study of cardiovascular and cancer pathophysiology. Summary: The high degree of genetic conservation between zebrafish and humans, as well as the ability to recapitulate cardiotoxic phenotypes observed in patients with cancer, make the zebrafish an effective model to study cancer therapy-associated cardiovascular toxicity. Though this model provides several key benefits over existing in vitro and in vivo models, limitations of the zebrafish model include the early developmental stage required for most high-throughput applications.

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Digoxin Enhances the Anticancer Effect on Non-Small Cell Lung Cancer While Reducing the Cardiotoxicity of Adriamycin

Cited by 51 publications

References 37 publications

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

Thevebioside, the Active Ingredient of Traditional Chinese Medicine, Inhibits SRC3 Mediated Signaling by Ubiquitination to Induce NSCLC Cells Apoptosis

Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity

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