scholarly journals Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1160 ◽  
Author(s):  
Anissa Nofita Sari ◽  
Priyanshu Bhargava ◽  
Jaspreet Kaur Dhanjal ◽  
Jayarani F. Putri ◽  
Navaneethan Radhakrishnan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Withania Somnifera ◽  
Catalytic Domain ◽  
Caffeic Acid Phenethyl Ester ◽  
Withaferin A ◽  
Selective Toxicity ◽  
Cervical Cancer Cells ◽  
Selective Death ◽  
And Function

We have earlier reported anticancer activity in Withaferin A (Wi-A), a withanolide derived from Ashwagandha (Withania somnifera) and caffeic acid phenethyl ester (CAPE), an active compound from New Zealand honeybee propolis. Whereas Wi-A was cytotoxic to both cancer and normal cells, CAPE has been shown to cause selective death of cancer cells. In the present study, we investigated the efficacy of Wi-A, CAPE, and their combination to ovarian and cervical cancer cells. Both Wi-A and CAPE were seen to activate tumor suppressor protein p53 by downregulation of mortalin and abrogation of its interactions with p53. Downregulation of mortalin translated to compromised mitochondria integrity and function that affected poly ADP-ribose polymerase1 (PARP1); a key regulator of DNA repair and protein-target for Olaparib, drugs clinically used for treatment of breast, ovarian and cervical cancers)-mediated DNA repair yielding growth arrest or apoptosis. Furthermore, we also compared the docking capability of Wi-A and CAPE to PARP1 and found that both of these could bind to the catalytic domain of PARP1, similar to Olaparib. We provide experimental evidences that (i) Wi-A and CAPE cause inactivation of PARP1-mediated DNA repair leading to accumulation of DNA damage and activation of apoptosis signaling by multiple ways, and (ii) a combination of Wi-A and CAPE offers selective toxicity and better potency to cancer cells.

scholarly journals Pharmacological Levels of Withaferin A (Withania somnifera) Trigger Clinically Relevant Anticancer Effects Specific to Triple Negative Breast Cancer Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e87850 ◽  
Author(s):  
Katarzyna Szarc vel Szic ◽  
Ken Op de Beeck ◽  
Dariusz Ratman ◽  
An Wouters ◽  
Ilse M. Beck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Withania Somnifera ◽  
Triple Negative ◽  
Withaferin A ◽  
Anticancer Effects

scholarly journals Targeting dePARylation selectively suppresses DNA repair–defective and PARP inhibitor–resistant malignancies

2019 ◽  
Vol 5 (4) ◽  
pp. eaav4340 ◽  
Author(s):  
Shih-Hsun Chen ◽  
Xiaochun Yu
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Topoisomerase I ◽  
Catalytic Domain ◽  
Alkylating Agents ◽  
Parp Inhibitor ◽  
Dna Lesions ◽  
Cancer Therapies

While poly(ADP-ribosyl)ation (PARylation) plays an important role in DNA repair, the role of dePARylation in DNA repair remains elusive. Here, we report that a novel small molecule identified from the NCI database, COH34, specifically inhibits poly(ADP-ribose) glycohydrolase (PARG), the major dePARylation enzyme, with nanomolar potency in vitro and in vivo. COH34 binds to the catalytic domain of PARG, thereby prolonging PARylation at DNA lesions and trapping DNA repair factors. This compound induces lethality in cancer cells with DNA repair defects and exhibits antitumor activity in xenograft mouse cancer models. Moreover, COH34 can sensitize tumor cells with DNA repair defects to other DNA-damaging agents, such as topoisomerase I inhibitors and DNA-alkylating agents, which are widely used in cancer chemotherapy. Notably, COH34 also efficiently kills PARP inhibitor–resistant cancer cells. Together, our study reveals the molecular mechanism of PARG in DNA repair and provides an effective strategy for future cancer therapies.

scholarly journals Olaparib modulates DNA repair efficiency, sensitizes cervical cancer cells to cisplatin and exhibits anti-metastatic property

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Chandra Bhushan Prasad ◽  
Shyam Babu Prasad ◽  
Suresh Singh Yadav ◽  
Laxmi Kant Pandey ◽  
Sunita Singh ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Repair ◽  
Cancer Cells ◽  
Repair Efficiency ◽  
Cervical Cancer Cells

scholarly journals Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells

FEBS Journal ◽  
2013 ◽  
Vol 280 (11) ◽  
pp. 2581-2593 ◽  
Author(s):  
Tzu-Hui Hsu ◽  
Chin-Chen Chu ◽  
Mei-Whey Hung ◽  
Hwei-Jen Lee ◽  
Hsien-Jun Hsu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Caffeic Acid ◽  
Caffeic Acid Phenethyl Ester ◽  
Cycle Arrest ◽  
Cervical Cancer Cells ◽  
Human Cervical Cancer Cells ◽  
Human Cervical Cancer

scholarly journals TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis

2021 ◽  
Author(s):  
Audrey Laurent ◽  
Thierry Madigou ◽  
Maud Bizot ◽  
Marion Turpin ◽  
Gaëlle Palierne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Catalytic Domain ◽  
Specific Gene ◽  
Lysosomal Storage ◽  
Binding Motifs ◽  
Lysosome Biogenesis ◽  
The One ◽  
And Function

Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression through controlling chromatin structure and accessibility to transcription factors. Cancer cells have their own transcriptional programs and we sought to alter such a cancer-specific program by enforcing expression of the catalytic domain (CD) of the methylcytosine dioxygenase TET2 in breast cancer cells. TET2 CD decreased the tumorigenic potential of cancer cells through both activation and repression of a repertoire of genes that, interestingly, differed in part from the one observed upon treatment with the hypomethylating agent decitabine. In addition to promoting the establishment of an antiviral state, TET2 activated 5mC turnover at thousands of MYC binding motifs and down-regulated a panel of known MYCrepressed genes involved in lysosome biogenesis and function. Thus, an extensive cross-talk between TET2 and the oncogenic transcription factor MYC establishes a lysosomal storage disease-like state that contributes to an exacerbated sensitivity to autophagy inducers.

Water-soluble amphiphilic ruthenium(ii) polypyridyl complexes as potential light-activated therapeutic agents

2020 ◽  
Vol 56 (65) ◽  
pp. 9332-9335
Author(s):  
Sandra Estalayo-Adrián ◽  
Salvador Blasco ◽  
Sandra A. Bright ◽  
Gavin J. McManus ◽  
Guillermo Orellana ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Therapeutic Agents ◽  
Water Soluble ◽  
Polypyridyl Complexes ◽  
Cervical Cancer Cells

Two new water-soluble amphiphilic Ru(ii) polypyridyl complexes were synthesised and their photophysical and photobiological properties evaluated; both complexes showed a rapid cellular uptake and phototoxicity against HeLa cervical cancer cells.

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