Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice

Panjamurthy, Kuppusamy; Nagalingam, Arumugam; Muniraj, Nethaji; Saxena, Neeraj K.; Sharma, Dipali

doi:10.1038/s41598-017-18190-4

Cited by 22 publications

(16 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AKT signaling FOX03a-Par-4 cell death pathway, ERK, and p38 pathway (Choi and Kim, 2015;Suman et al, 2016;Kuppusamy et al, 2017) inhibited the kinase activity of pyruvate dehydrogenase kinase 1 (PDK1), shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of ROS, attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability of SKOV3 cells. Notably, DIC (32 mg/kg) was found safe toward ovarian tissues and developing oocytes; implicating importance of DIC as a potential anticancer agent when female fertility preservation is a concern (Aras et al, 2016).…”

Section: Phytochemicals In Pre-clinical Trialsmentioning

confidence: 99%

“…Similarly, in another study, oral administration of WA (4 mg/kg) effectively inhibited HepG2-xenografts and diethylnitrosamine (DEN)-induced-hepatocellular carcinoma (HCC) in C57BL/6 mice by elevating the levels of ERK, RSK, ELK1, and DR5 along with decreased expression of Ki67. The in vitro molecular mechanism studies suggested WA increased phosphorylation of ERK and p38 leading to increased phosphorylation of p90-ribosomal S6 kinase (RSK) and a concomitant activation of ETS-like transcription factor-1 (ELK1) and death receptor protein-5 (DR5) (Kuppusamy et al, 2017).…”

Section: Phytochemicals In Pre-clinical Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Phytochemicals In Pre-clinical Trialsmentioning

confidence: 99%

Section: Phytochemicals In Pre-clinical Trialsmentioning

confidence: 99%

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Previous study from our lab showed the growth-inhibitory and pro-apoptotic effects of WFA in HepG2 and Huh7 cells [28]. Evaluation of anti-proliferative efficacy of WFA on multiple HCC cells showed that WFA treatment significantly decreased the anchorage-dependent cell viability of multiple HCC cells in a dose-dependent manner, with an IC50 of 5 µM in Huh7, HepG2 and MHCC97L cells; and 7.5 µM in MHCC97H cells, respectively (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Acting as a potential c-Met inhibitor, WFA inhibits stemness in pancreatic cancer [25] and also inhibits epithelial-mesenchymal transition in non-small cell lung cancer cells [26]. Phosphokinase array analyses revealed that WFA activates ERK/RSK axis and mediates growth inhibition via death receptor 5 (DR5) upregulation [27,28]. Withania somnifera extract is being investigated for its efficacy for anxiety, schizophrenia and bipolar disorder in clinic (ClinicalTrials.gov Identifier: NCT00761761, NCT01311180, NCT01793935) and has been reported to have clinical benefits for schizophrenia [29].…”

Section: Introductionmentioning

confidence: 99%

Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma

Siddharth

Muniraj

Saxena

et al. 2019

Cancers

Self Cite

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality, and despite recent advances in early diagnosis and therapeutics, HCC related morbidity and mortality rate continue to rise. Clearly, it is imperative to develop novel effective therapies for HCC to improve long-term survival of HCC patients. We found that Withaferin A (WFA), a bioactive compound derived from Withania somnifera, is an effective agent for HCC inhibition. Interestingly, we observed that in addition to inducing apoptotic cell death, WFA also induces autophagy in HCC cells. Utilizing mRFP-EGFP-LC3B, LC3B-GFP/Lysotracker and LC3B-GFP/Rab7-RFP, we show that WFA induces autophagosomes-lysosomes fusion. WFA-induced autolysosomes exhibit intact protein degradation activity as evident with cathepsin-D activation and DQ-BSA assays. Importantly, we present that inhibiting WFA-induced autophagy either by blocking autophagosome-formation or by elevating lysosomal pH (Chloroquine and Bafilomycin) enhances WFA-induced growth-inhibition and apoptosis, indicating the presence of cytoprotective autophagy. Indeed, WFA and CQ combination shows synergism and higher efficacy in comparison to either monotherapy. Collectively, we reveal that the efficacy of WFA is somewhat diminished by the concomitant induction of cytoprotective autophagy which can be successfully conquered by cotreatment with CQ, and we pave the way for development of a novel combination therapeutic strategy for HCC.

show abstract

“…To be specific, the average age of diagnosis is 65 and has gradually shifted to early diagnosis over the past decade, and males are more likely to suffer HCC than females . It is reported that patients with HCC has low 5‐year survival rate (~16%) partly due to the lack of effective therapeutic methods . Thus, it is very urgent to find new therapeutic methods for HCC treatment.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in NRG 1 gene and risk of post‐traumatic stress disorders in patients with hepatocellular carcinoma

Luo

Guo

et al. 2020

Clinical Laboratory Analysis

View full text Add to dashboard Cite

Objective: Neuregulin 1 (NRG1) was proved to play an important role in numerous neurodevelopmental processes. In our study, we aimed to investigate the relationship between the NRG1 gene polymorphism and the cognitive function of patients with hepatocellular carcinoma (HCC) complicated with post-traumatic stress disorders (PTSD) before and after the psychological intervention. Methods: Mini-mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Loewenstein Occupational Therapy Cognitive Assessment (LOTCA)were used for cognitive function assessment. Serum level of NRG1 was detected by ELISA, and the correlation between NRG1 level and cognitive function was analyzed.The difference of cognitive function score of patients with HCC complicated with PTSD before and after psychological intervention was compared, and the relationship between rs35753505 and rs3924999 polymorphism with the score was analyzed. Results:Patients with HCC complicated with PTSD showed decreased serum NRG1 level. NRG1 levels of patients in the HCC + PTSD group were positively correlated with MMSE, MoCA, and LOTCA scores. In rs35753505, the CC genotype was a risk factor for the occurrence of PTSD in patients with HCC, while in rs3924999, the GG genotype was a risk factor for the occurrence of PTSD in patients with HCC. After psychological intervention, the CC genotype at rs35753505 and the GG genotype at rs3924999 were susceptible genotypes.Conclusion: CC genotype at rs35753505 and GG genotype at rs3924999 of NRG1 gene increased the risk of PTSD in patients with HCC. CC and GG genotypes were susceptible after psychological intervention. K E Y W O R D Shepatocellular carcinoma, NRG1, post-traumatic stress disorders, rs35753505, rs3924999

show abstract

Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice

Cited by 22 publications

References 46 publications

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma

Genetic variation in NRG 1 gene and risk of post‐traumatic stress disorders in patients with hepatocellular carcinoma

Contact Info

Product

Resources

About