Ethonafide-Induced Cytotoxicity Is Mediated by Topoisomerase II Inhibition in Prostate Cancer Cells

Pourpak, Alan; Landowski, Terry H.; Dorr, Robert T.

doi:10.1124/jpet.106.117457

Cited by 17 publications

(16 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ethonafide has been previously shown to stabilize both topoIIα-and topoIIβ-DNA complexes (21), however the primary DSB formation and cytotoxicity of the agent has been attributed to inhibition of topoIIα, whereas proteasomal processing of topoII-DNA covalent complex processing is more efficient in topoIIβ complexes.…”

Section: Discussionmentioning

confidence: 99%

“…This agent is a member of the azonafide series of anthracenebased DNA intercalating antitumor agents (20). Mechanistically, ethonafide inhibits topo II activity by stabilizing a covalent complex between topoisomerase II and DNA, known as the cleavable complex, making ethonafide a topo II poison (21). In the present study, we examined the effects of ethonafide in combination with sub-cytotoxic doses of bortezomib as a strategy to potentiate the activity of ethonafide in drug resistant myeloma cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracenecontaining topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-hour treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Overall, these results demonstrated that this 6-ethoxy substituted azonafide had consistent experimental anti-tumor activity against human cancers and was considered of potential to treat patients with MDR tumors. Pourpak et al [45] further demonstrated that ethonafide was active against human prostate cancer cell lines in vitro and in vivo. Importantly, ethonafide was better tolerated, with equal or greater activity than mitoxantrone in SCID mice grafted with human DU-145 prostate cancer cells.…”

Section: Preclinical In Vivo Activitymentioning

confidence: 92%

“…Further studies have shown that this agent produces DNA single and double strand breaks, DNAprotein cross-links characteristic of topo II inhibition, as well as catalytic inhibition of topo II activity [58]. Pourpak et al [45] found that the azonafide derivative ethonafide (128) inhibited topo II activity by stabilizing the enzyme-DNA complex, involving both topo II and . In addition, the compound induced a potent G2 cell cycle arrest in the human DU-145 prostate cancer cell line.…”

Section: A) Topoisomerase II Inhibitionmentioning

confidence: 98%

Naphthalimides and Azonafides as Promising Anti-Cancer Agents

Ingrassia¹,

Lefranc²,

Kiss³

et al. 2009

CMC

134

View full text Add to dashboard Cite

Naphthalimides, a class of compounds which bind to DNA by intercalation, have shown high anti-cancer activity against a variety of murine and more notably human cancer cell lines. Azonafide derivatives are also potential anti-tumor agents which are structurally related to the naphthalimides. Derivatives of azonafide have shown enhanced activity against various cancer models, especially leukemias, breast cancer and melanoma. Naphthalimides in general and amonafide in particular, are most probably the agents which have been involved in the greatest number of clinical trials without ever acceding to the market because of dose-limiting toxicity. This statement also reflects the immense interest that oncologists have paid to this class of compounds with respect to their anti-cancer potential. While the first generation of naphthalimides were mainly topoisomerse II poisons, some new compounds display novel mechanism of action. In contrast to the most widely used topo II poisons, including etoposide, adriamycin and their analogues, which often induce multi-drug resistance, several naphthalimide-related compounds have been reported not to be affected by this phenomenon. Multi-disciplinary approaches including medicinal chemistry, early toxicology and DMPK, in vivo activity assessment in diverse preclinical models and in-depth mechanism of action deciphering, along with the lessons learnt from previous and currently ongoing clinical trials, have resulted in the generation of a number of novel promising naphthalimide derivatives. It is thus reasonable to expect that members of this class of compounds will reach the oncology market in the near future.

show abstract

“…Amonafide, among other intercalating agents, has the ability to inhibit the activity of topoisomerases I and II, preventing the enzyme's capability to catalyze cleavage of DNA [31,32]. This topoisomerase activity serves as the foundation for sensitive DNA intercalation tests for non-alkylating amonafide derivatives.…”

Section: Dna Alkylation: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

et al. 2015

View full text Add to dashboard Cite

Research on DNA binding antitumor agents has been classically steered by either non-covalent (DNA intercalation) or covalent (DNA alkylation) interactions. In this context bi-functional anticancer molecules are particularly attractive since they are capable of sequential DNA intercalation followed by DNA alkylation. Here we describe the synthesis and in vitro anticancer activity of bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives. Cell viability assays indicate that our amonafide-N-mustard chimeras are selective, effective only on certain tumor cell lines, and less toxic toward nonmalignant cells than the drug amonafide. The biological activities of the bi-functional derivatives presented here are encouraging and the compounds are suitable for further optimization and in vivo studies. Graphical Abstract Here we describe the synthesis and in vitro anticancer activity of three bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives presenting both DNA intercalation and alkylation capabilities. Cell viability assays indicate that these amonafide-N-mustard chimeras are effective only on certain tumor cell lines and are less toxic towards non-malignant cells than their parent drug: amonafide.Electronic supplementary material The online version of this article (

show abstract

Ethonafide-Induced Cytotoxicity Is Mediated by Topoisomerase II Inhibition in Prostate Cancer Cells

Cited by 17 publications

References 35 publications

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Naphthalimides and Azonafides as Promising Anti-Cancer Agents

Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

Contact Info

Product

Resources

About