scholarly journals Cooperative TRAIL production mediates IFNα/Smac mimetic-induced cell death in TNFα-resistant solid cancer cells

Oncotarget ◽  
2016 ◽  
Vol 7 (4) ◽  
pp. 3709-3725 ◽  
Author(s):  
Stefanie Roesler ◽  
Ines Eckhardt ◽  
Sebastian Wolf ◽  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Solid Cancer ◽  
Smac Mimetic

scholarly journals Pharmacotranscriptomic Analysis Reveals Novel Drugs and Gene Networks Regulating Ferroptosis in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3273 ◽  
Author(s):  
Haitang Yang ◽  
Liang Zhao ◽  
Yanyun Gao ◽  
Feng Yao ◽  
Thomas M. Marti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Gene Networks ◽  
Drug Effects ◽  
Gene Signature ◽  
Solid Cancer ◽  
Gene Signatures ◽  
Drug Candidates ◽  
Drug Compounds

(1) Background: Ferroptosis is an apoptosis-independent cell death program implicated in many diseases including cancer. Emerging evidence suggests ferroptosis as a promising avenue for cancer therapy, but the paucity of mechanistic understanding of ferroptosis regulation and lack of biomarkers for sensitivity to ferroptosis inducers have significantly hampered the utility of ferroptosis-based therapy. (2) Methods: We performed integrated dataset analysis by correlating the sensitivity of small-molecule compounds (n = 481) against the transcriptomes of solid cancer cell lines (n = 659) to identify drug candidates with the potential to induce ferroptosis. Generalizable gene signatures of ferroptosis sensitivity and resistance are defined by interrogating drug effects of ferroptosis inducers (n = 7) with transcriptomic data of pan-solid cancer cells. (3) Results: We report, for the first time, the comprehensive identification of drug compounds that induce ferroptosis and the delineation of generalizable gene signatures of pro- and anti-ferroptosis in pan-cancer. We further reveal that small cell lung cancer (SCLC) and isocitrate dehydrogenase (IDH1/2)-mutant brain tumors show enrichment of pro-ferroptosis gene signature, suggesting a unique vulnerability of SCLC and IDH-mutant tumors to ferroptosis inducers. Finally, we demonstrate that targeting class I histone deacetylase (HDAC) significantly enhances ferroptotic cell death caused by Erastin, an ferroptosis inducer, in lung cancer cells, revealing a previously underappreciated role for HDAC in ferroptosis regulation. (4) Conclusions: Our work reveals novel drug compounds and gene networks that regulate ferroptosis in cancer, which sheds light on the mechanisms of ferroptosis and may facilitate biomarker-guided stratification for ferroptosis-based therapy.

scholarly journals Smac-mimetic enhances antitumor effect of standard chemotherapy in ovarian cancer models via Caspase 8-independent mechanism

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Lidia F. Hernandez ◽  
Angie B. Dull ◽  
Soumya Korrapati ◽  
Christina M. Annunziata
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Cell Death ◽  
Cancer Cells ◽  
Caspase 8 ◽  
Wild Type ◽  
Tumor Cell Death ◽  
Standard Chemotherapy ◽  
Smac Mimetic ◽  
Vitro Effect

AbstractOvarian cancer is the most lethal gynecological cancer in the US. Standard treatment consists of surgery followed by chemotherapies relying on apoptotic tumor cell death. Most women with advanced stage disease will relapse, suggesting that this disease is characterized by primary and acquired resistance to chemotherapy, and novel approaches to treatment are greatly needed. Low Caspase 8 expression levels in ovarian cancers correlate with resistance to apoptotic chemotherapy, and a subpopulation of patients with low Caspase 8 levels exhibit poorer overall survival after standard-of-care treatment. We hypothesized that low Caspase 8 function reduces the ability of cancer cells to undergo apoptosis when exposed to standard chemotherapy and that second mitochondria-derived activator of caspases (Smac)-mimetics could increase cell death in combination with chemotherapy. Here we show that combination treatment with a Smac-mimetic can target tumor cells with low Caspase 8 and induce necroptotic cell death. We investigated the in vitro effect of Smac-mimetic added to carboplatin and paclitaxel treatment of ovarian cancer cells expressing wild type and low Caspase 8 levels, which resulted in a 2–4-fold enhancement of cell death. Mice bearing subcutaneous or intraperitoneal ovarian xenografts showed greater aggressiveness of Caspase 8-deficient versus wild-type tumors; combined in vivo treatment with chemotherapy and Smac-mimetic resulted in >50% decrease in low Caspase 8 xenograft growth, as well as significantly enhanced overall survival, especially when given simultaneously with paclitaxel. Surprisingly, Smac-mimetic on the same day as carboplatin decreased mouse survival compared to when it was given on a sequential day of treatment. The antagonism was associated with a decrease in DNA damage markers, emphasizing the importance of optimizing timing of drug administration. Clinical validation of such approaches is needed to increase the effectiveness of current standard ovarian cancer treatment.

Glycolytic inhibitor induces metabolic crisis in solid cancer cells to enhance cold plasma‐induced cell death

2021 ◽  
Author(s):  
Nagendra K. Kaushik ◽  
Neha Kaushik ◽  
Pradeep Bhartiya ◽  
Linh N. Nguyen ◽  
Eun H. Choi
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cold Plasma ◽  
Solid Cancer ◽  
Metabolic Crisis ◽  
Glycolytic Inhibitor

Activation of the intrinsic-apoptotic pathway in LNCaP prostate cancer cells by genistein- topotecan combination treatments

2013 ◽  
Vol 3 (3) ◽  
pp. 66 ◽  
Author(s):  
Vanessa Hörmann ◽  
Sivanesan Dhandayuthapani ◽  
James Kumi-Diaka ◽  
Appu Rathinavelu
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Treatment Options ◽  
Attractive Alternative ◽  
Intrinsic Apoptotic Pathway ◽  
Prostate Cancer Cells ◽  
Apoptotic Pathway ◽  
Combination Treatments

Background: Prostate cancer is the second most common cancer in American men. The development of alternative preventative and/or treatment options utilizing a combination of phytochemicals and chemotherapeutic drugs could be an attractive alternative compared to conventional carcinoma treatments. Genistein isoflavone is the primary dietary phytochemical found in soy and has demonstrated anti-tumor activities in LNCaP prostate cancer cells. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy for secondary treatment of lung, ovarian and cervical cancers. The purpose of this study was to detail the potential activation of the intrinsic apoptotic pathway in LNCaP prostate cancer cells through genistein-topotecan combination treatments. Methods: LNCaP cells were cultured in complete RPMI medium in a monolayer (70-80% confluency) at 37ºC and 5% CO2. Treatment consisted of single and combination groups of genistein and topotecan for 24 hours. The treated cells were assayed for i) growth inhibition through trypan blue exclusion assay and microphotography, ii) classification of cellular death through acridine/ ethidium bromide fluorescent staining, and iii) activation of the intrinsic apoptotic pathway through Jc-1: mitochondrial membrane potential assay, cytochrome c release and Bcl-2 protein expression.Results: The overall data indicated that genistein-topotecan combination was significantly more efficacious in reducing the prostate carcinoma’s viability compared to the single treatment options. In all treatment groups, cell death occurred primarily through the activation of the intrinsic apoptotic pathway.Conclusion: The combination of topotecan and genistein has the potential to lead to treatment options with equal therapeutic efficiency as traditional chemo- and radiation therapies, but lower cell cytotoxicity and fewer side effects in patients. Key words: topotecan; genistein; intrinsic apoptotic cell death

Oxyresveratrol drives caspase-independent apoptosis-like cell death in MDA-MB-231 breast cancer cells through the induction of ROS

2020 ◽  
Vol 173 ◽  
pp. 113724 ◽  
Author(s):  
Damu Sunilkumar ◽  
G. Drishya ◽  
Aneesh Chandrasekharan ◽  
Sanu K. Shaji ◽  
Chinchu Bose ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells
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