The Chemotherapeutic Agents XK469 (2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-Bromo-2-quinolinyl)oxy]phenoxy}propionic acid) Inhibit Cytokinesis and Promote Polyploidy and Induce Senescence

Reiners, John J.; Kleinman, Miriam D.; Joiakim, Aby; Mathieu, Patricia

doi:10.1124/jpet.108.144808

Cited by 10 publications

(7 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…XK469 (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 ([2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}]propionic acid) are two chemotherapeutic agents that are effective against a broad range of human tumors and related to the induction of cell cycle arrest and a mixed autophagy and apoptosis profile. [49] In the present study, the treatment with quinoxaline 4 led to a reduction of the cell volume of the epimastigotes and did not induce severe alterations in the cell membrane integrity of the three parasite forms at the maximum concentration tested (7.4 µM). This was also confirmed by the TEM analysis of the epimastigotes, showing that the majority of the cells had a well-preserved external membrane, even when the inside of the cell was completely altered.…”

Section: Discussionsupporting

confidence: 46%

A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

et al. 2014

View full text Add to dashboard Cite

BackgroundChagas’ disease is a condition caused by the protozoan Trypanosoma cruzi that affects millions of people, mainly in Latin America where it is considered endemic. The chemotherapy for Chagas disease remains a problem; the standard treatment currently relies on a single drug, benznidazole, which unfortunately induces several side effects and it is not successful in the cure of most of the chronic patients. In order to improve the drug armamentarium against Chagas’ disease, in the present study we describe the synthesis of the compound 3-chloro-7-methoxy-2-(methylsulfonyl) quinoxaline (quinoxaline 4) and its activity, alone or in combination with benznidazole, against Trypanosoma cruzi in vitro.Methodology/Principal FindingsQuinoxaline 4 was found to be strongly active against Trypanosoma cruzi Y strain and more effective against the proliferative forms. The cytotoxicity against LLCMK2 cells provided selective indices above one for all of the parasite forms. The drug induced very low hemolysis, but its anti-protozoan activity was partially inhibited when mouse blood was added in the experiment against trypomastigotes, an effect that was specifically related to blood cells. A synergistic effect between quinoxaline 4 and benznidazole was observed against epimastigotes and trypomastigotes, accompanied by an antagonistic interaction against LLCMK2 cells. Quinoxaline 4 induced several ultrastructural alterations, including formations of vesicular bodies, profiles of reticulum endoplasmic surrounding organelles and disorganization of Golgi complex. These alterations were also companied by cell volume reduction and maintenance of cell membrane integrity of treated-parasites.Conclusion/SignificanceOur results demonstrated that quinoxaline 4, alone or in combination with benznidazole, has promising effects against all the main forms of T. cruzi. The compound at low concentrations induced several ultrastructural alterations and led the parasite to an autophagic-like cell death. Taken together these results may support the further development of a combination therapy as an alternative more effective in Chagas’ disease treatment.

show abstract

Section: Discussionsupporting

confidence: 46%

A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Selective inhibitors of topoisomerase II, an enzyme essential for separation of newly replicated chromatids, promote the accumulation of tetraploid and polyploid cells (30–32). Of the eight topoisomerase inhibitors in the LOPAC 1280 , only etoposide (#8), ellipticine (#30) and XK469 (#40 Table I, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For similar reasons, compounds that inhibit topoisomerase II, an enzyme essential for separation of newly replicated chromatids, also exhibited some activity on both SW480 and MCF10A cells (#8, 30, 40 Table I). In fact, all three inhibitors have been reported to promote the accumulation of polyploid cells (30–32). In contrast, the five LOPAC 1280 compounds that inhibit topoisomerase I, an enzyme essential for replication fork activity, did not induce excess DNA replication, thereby confirming that only those compounds that inhibit topoisomerase II specifically induce excess DNA replication.…”

Section: Discussionmentioning

confidence: 99%

An Image-Based, High-Throughput Screening Assay for Molecules that Induce Excess DNA Replication in Human Cancer Cells

Zhu

Lee

Johnson

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

Previous studies have shown DNA re-replication can be induced in cells derived from human cancers under conditions in which it is not possible for cells derived from normal tissues. Because DNA re-replication induces cell death, this strategy could be applied to the discovery of potential anticancer therapeutics. Therefore, an imaging assay amenable to high-throughput screening was developed that measures DNA replication in excess of four genomic equivalents in the nuclei of intact cells and indexes cell proliferation. This assay was validated by screening a library of 1,280 bioactive molecules on both normal and tumor-derived cells where it proved more sensitive than current methods for detecting excess DNA replication. This screen identified known inducers of excess DNA replication, such as inhibitors of microtubule dynamics, and novel compounds that induced excess DNA replication in both normal and cancer cells. In addition, two compounds were identified that induced excess DNA replication selectively in cancer cells and one that induced endocycles selectively in cancer cells. Thus, this assay provides a new approach to the discovery of compounds useful for investigating the regulation of genome duplication and for the treatment of cancer. Mol Cancer Res; 9(3); 294-310. Ó2011 AACR.

show abstract

“…Melanocytes can undergo senescence due to increased polyploidy and subsequent autophagy activation during treatment with chemotherapeutic agents [56]. In contrast, loss of ATG7 results in melanocyte senescence and prevents melanoma development in BRAF V600E /PTEN-null mice, supporting a pro-tumorigenic role for autophagy [57].…”

Section: Role Of Autophagymentioning

confidence: 99%

Autophagy: In the cROSshairs of cancer

Hambright

Ghosh

2017

Biochemical Pharmacology

View full text Add to dashboard Cite

Two prominent features of tumors that contribute to oncogenic survival signaling are redox disruption, or oxidative stress phenotype, and high autophagy signaling, making both phenomena ideal therapeutic targets. However, the relationship between redox disruption and autophagy signaling is not well characterized and the clinical impact of reactive oxygen species (ROS)-generating chemotherapeutics on autophagy merits immediate attention as autophagy largely contributes to chemotherapeutic resistance. In this commentary we focus on melanoma, using it as an example to provide clarity to current literature regarding the roles of autophagy and redox signaling which can be applicable to initiation and maintenance of most tumor types. Further, we address the crosstalk between ROS and autophagy signaling during pharmacological intervention and cell fate decisions. We attempt to elucidate the role of autophagy in regulating cell fate following treatment with ROS-generating agents in preclinical and clinical settings and discuss the emerging role of autophagy in cell fate decisions and as a cell death mechanism. We also address technical aspects of redox and autophagy evaluation in experimental design and data interpretation. Lastly, we present a provocative view of the clinical relevance, emerging challenges in dual targeting of redox and autophagy pathways for therapy, and the future directions to be addressed in order to advance both basic and translational aspects of this field.

show abstract

The Chemotherapeutic Agents XK469 (2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-Bromo-2-quinolinyl)oxy]phenoxy}propionic acid) Inhibit Cytokinesis and Promote Polyploidy and Induce Senescence

Cited by 10 publications

References 38 publications

A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

An Image-Based, High-Throughput Screening Assay for Molecules that Induce Excess DNA Replication in Human Cancer Cells

Autophagy: In the cROSshairs of cancer

Contact Info

Product

Resources

About