scholarly journals Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3675
Author(s):  
Victor M. Matias-Barrios ◽  
Mariia Radaeva ◽  
Chia-Hao Ho ◽  
Joseph Lee ◽  
Hans Adomat ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Topoisomerase Ii ◽  
Dna Interaction ◽  
Drug Candidate ◽  
Secondary Malignancy ◽  
Cancer Cell Growth ◽  
Drug Induced ◽  
Cancer Cell Death ◽  
Control Tumor Growth ◽  
Control Tumor

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

scholarly journals Discovery of New Catalytic Topoisomerase II Inhibitors for Anticancer Therapeutics

2021 ◽  
Vol 10 ◽  
Author(s):  
Victor M. Matias-Barrios ◽  
Mariia Radaeva ◽  
Yi Song ◽  
Zaccary Alperstein ◽  
Ahn R. Lee ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Cancer Cell ◽  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Secondary Malignancy ◽  
Cancer Cell Proliferation ◽  
Cancer Cell Growth ◽  
Cancer Cell Death ◽  
Low Cytotoxicity

Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.

scholarly journals Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth: Implications for therapy

2007 ◽  
Vol 6 (5) ◽  
pp. 795-801 ◽  
Author(s):  
Dineo Khabele ◽  
Deok-Soo Son ◽  
Angelika K. Parl ◽  
Gary L. Goldberg ◽  
Leonard H. Augenlicht ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Growth ◽  
Gene Silencing ◽  
Cancer Cell ◽  
Histone Deacetylases ◽  
Ovarian Cancer Cell ◽  
Class I ◽  
Cancer Cell Growth ◽  
Drug Induced ◽  
Or Gene

Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death

2012 ◽  
Vol 132 (10) ◽  
pp. 2248-2257 ◽  
Author(s):  
Laura Conradt ◽  
Annika Henrich ◽  
Matthias Wirth ◽  
Maximilian Reichert ◽  
Marina Lesina ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Cancer Cell ◽  
Topoisomerase Ii ◽  
Pancreatic Cancer Cell ◽  
Topoisomerase Ii Inhibitors ◽  
Cancer Cell Death

Regulation by survivin of cancer cell death induced by F14512, a polyamine-containing inhibitor of DNA topoisomerase II

APOPTOSIS ◽  
2011 ◽  
Vol 17 (4) ◽  
pp. 364-376 ◽  
Author(s):  
Caroline Ballot ◽  
Manel Jendoubi ◽  
Jérome Kluza ◽  
Aurélie Jonneaux ◽  
William Laine ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Cancer Cell Death

scholarly journals Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death

2017 ◽  
Vol 8 (6) ◽  
pp. e2848-e2848 ◽  
Author(s):  
Emarndeena H Cheteh ◽  
Martin Augsten ◽  
Helene Rundqvist ◽  
Julie Bianchi ◽  
Victoria Sarne ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Human Cancer ◽  
Cancer Associated Fibroblasts ◽  
Drug Induced ◽  
Cancer Cell Death

scholarly journals An Increase in Reactive Oxygen Species by Deregulation of ARNT Enhances Chemotherapeutic Drug-Induced Cancer Cell Death

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e99242 ◽  
Author(s):  
Jiunn-Min Shieh ◽  
Chih-Jie Shen ◽  
Wei-Chiao Chang ◽  
Hung-Chi Cheng ◽  
Ya-Yi Chan ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cancer Cell ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Chemotherapeutic Drug ◽  
Drug Induced ◽  
Cancer Cell Death

scholarly journals Drug-adapted cancer cell lines reveal drug-induced heterogeneity and enable the identification of biomarker candidates for the acquired resistance setting

2020 ◽  
Author(s):  
Martin Michaelis ◽  
Mark N. Wass ◽  
Ian Reddin ◽  
Yvonne Voges ◽  
Florian Rothweiler ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Neuroblastoma Cell ◽  
Acquired Resistance ◽  
Cancer Therapeutics ◽  
Neuroblastoma Cell Line ◽  
Response To Treatment ◽  
Drug Candidate ◽  
Intrinsic Resistance ◽  
Drug Induced ◽  
Response Data

AbstractSurvivin is a drug target and the survivin suppressant YM155 a drug candidate for high-risk neuroblastoma. Findings from one YM155-adapted subline of the neuroblastoma cell line UKF-NB-3 had suggested that increased ABCB1 (mediates YM155 efflux) levels, decreased SLC35F2 (mediates YM155 uptake) levels, decreased survivin levels, and TP53 mutations indicate YM155 resistance. Here, the investigation of ten additional YM155-adapted UKF-NB-3 sublines only confirmed the roles of ABCB1 and SLC35F2. However, cellular ABCB1 and SLC35F2 levels did not indicate YM155 sensitivity in YM155-naïve cells, as indicated by drug response data derived from the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) databases. Moreover, the resistant sublines were characterised by a remarkable heterogeneity. Only seven sublines developed on-target resistance as indicated by resistance to RNAi-mediated survivin depletion. The sublines also varied in their response to other anti-cancer drugs. In conclusion, cancer cell populations of limited intrinsic heterogeneity can develop various resistance phenotypes in response to treatment. Therefore, individualised therapies will require monitoring of cancer cell evolution in response to treatment. Moreover, biomarkers can indicate resistance formation in the acquired resistance setting, even when they are not predictive in the intrinsic resistance setting.

scholarly journals Autophagy in Cancer Cell Death

Biology ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 82 ◽  
Author(s):  
Linder ◽  
Kögel
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Drug Induced ◽  
Cancer Cell Death ◽  
Cell Death Program ◽  
Cellular Context ◽  
Dependent Cell ◽  
Developmental Cell Death ◽  
Cellular Components

Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.

scholarly journals Small Molecule Binds with Lymphocyte Antigen 6K to Induce Cancer Cell Death

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 509 ◽  
Author(s):  
Senyi Benti ◽  
Purushottam B. Tiwari ◽  
Dustin W. Goodlett ◽  
Leily Daneshian ◽  
Grant B. Kern ◽  
...  
Keyword(s):  
Head And Neck ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Small Molecule ◽  
Breast Cancers ◽  
Cancer Cell Growth ◽  
Lymphocyte Antigen ◽  
Pharmacological Inhibition ◽  
Cancer Cell Death ◽  
Small Molecule Libraries

Elevated gene expression of Lymphocyte antigen 6K (LY6K) in cancer cells is associated with poor survival outcomes in multiple different cancer types including cervical, breast, ovarian, lung, and head and neck cancer. Since inhibition of LY6K expression inhibits cancer cell growth, we set out to explore whether pharmacological inhibition of LY6K could produce the same effect. We screened small molecule libraries for direct binding to recombinant LY6K protein in a surface plasmon resonance assay. We found that NSC243928 directly binds to the full-length and mature forms of LY6K and inhibits growth of HeLa cells that express LY6K. NSC243928 did not display binding with LY6D or LY6E. Our data demonstrate a first-time proof of principle study that pharmacological inhibition of LY6K using small molecules in cancer cells is a valid approach to developing targeted therapies against LY6K. This approach will be specifically relevant in hard-to-treat cancers where LY6K is highly expressed, such as cervical, pancreatic, ovarian, head and neck, lung, gastric, and triple-negative breast cancers.

scholarly journals PKM2 Regulates HSP90-Mediated Stability of the IGF-1R Precursor Protein and Promotes Cancer Cell Survival during Hypoxia

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3850
Author(s):  
Han Koo ◽  
Sangwon Byun ◽  
Jieun Seo ◽  
Yuri Jung ◽  
Dong Chul Lee ◽  
...  
Keyword(s):  
Cell Growth ◽  
Protein Expression ◽  
Cancer Cell ◽  
Heat Shock Protein 90 ◽  
Cancer Cell Growth ◽  
Growth And Survival ◽  
Lung Cancer Patients ◽  
Hypoxic Conditions ◽  
Cancer Cell Death ◽  
Cell Growth And Survival

Insulin-like growth factor-1 receptor (IGF-1R), an important factor in promoting cancer cell growth and survival, is commonly upregulated in cancer cells. However, amplification of the IGF1R gene is extremely rare in tumors. Here, we have provided insights into the mechanisms underlying the regulation of IGF-1R protein expression. We found that PKM2 serves as a non-metabolic protein that binds to and increases IGF-1R protein expression by promoting the interaction between IGF-1R and heat-shock protein 90 (HSP90). PKM2 depletion decreases HSP90 binding to IGF-1R precursor, thereby reducing IGF-1R precursor stability and the basal level of mature IGF-1R. Consequently, PKM2 knockdown inhibits the activation of AKT, the key downstream effector of IGF-1R signaling, and increases apoptotic cancer cell death during hypoxia. Notably, we clinically verified the PKM2-regulated expression of IGF-1R through immunohistochemical staining in a tissue microarray of 112 lung cancer patients, demonstrating a significant positive correlation (r = 0.5208, p < 0.0001) between PKM2 and IGF-1R expression. Together, the results of a previous report demonstrated that AKT mediates PKM2 phosphorylation at serine-202; these results suggest that IGF-1R signaling and PKM2 mutually regulate each other to facilitate cell growth and survival, particularly under hypoxic conditions, in solid tumors with dysregulated IGF-1R expression.

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