Molecular and biochemical pharmacology of mitoxantrone

Durr, Frederick E.; Wallace, Roslyn E.; Citarella, R. V.

doi:10.1016/0305-7372(83)90016-6

Cited by 109 publications

(56 citation statements)

References 10 publications

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“…(b) An increase of HIF1a mRNA levels in the polysomal fractions but a decrease of HIF-1a translation in the presence of mitoxantrone suggests that mitoxantrone affects translation elongation. Mitoxantrone is known to intercalate between base pairs of the DNA helix with a G-C preference (41,42) and has been shown to stabilize the tau pre-mRNA stem loop structure and alter tau mRNA splicing by intercalating between 2 G-C base pairs (43). The secondary structure predicted by RNAfold software reveals many G-C base pairs in HIF-1a mRNA, which supports the possibility that mitoxantrone may intercalate into HIF-1a mRNA.…”

Section: Discussionmentioning

confidence: 73%

Mitoxantrone Inhibits HIF-1α Expression in a Topoisomerase II–Independent Pathway

Toh

2011

Clinical Cancer Research

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Purpose: Solid tumors encounter a growth-limiting hypoxic microenvironment as they develop. Hypoxiainducible factors (HIF) play important roles in hypoxia-associated tumor development and therapeutic resistance. Targeting the HIF pathway (especially HIF-1a) represents a promising cancer treatment strategy. Here, we report a novel class of HIF-1a inhibitors and the possible molecular basis of inhibition.Experimental Design: We analyzed the inhibitory effects of clinically used topoisomerase II (TOP2)-targeting drugs on HIF-1a expression with a primary focus on mitoxantrone. The potential role of TOP2 in mitoxantrone-inhibited HIF-1a expression was studied using pharmacologic inhibition, a knockdown approach, and TOP2 mutant cells. Moreover, involvement of mitoxantrone in proteasome-mediated degradation, transcription, and translation of HIF-1a was examined.Results: The TOP2-targeting mitoxantrone, but neither doxorubicin nor etoposide (VP-16), strongly inhibited HIF-1a expression under hypoxic conditions in a dose-and time-dependent manner. Surprisingly, the mitoxantrone-mediated inhibition of HIF-1a expression was largely independent of two TOP2 isozymes, proteasomal degradation, and transcription. Furthermore, mitoxantrone inhibited HIF-1a expression and function in a similar fashion as cycloheximide, suggesting that mitoxantrone might inhibit HIF-1a via a blockage at its translation step. In vitro translation experiments using HIF-1a mRNA further confirmed inhibition of HIF-1a translation by mitoxantrone. Interestingly, levels of the polysome-bound HIF-1a and VEGF-A mRNA were elevated and decreased after mitoxantrone treatment, respectively.Conclusions: We have identified the TOP2-targeting compound, mitoxantrone, as an HIF-1a inhibitor possibly through a translation inhibition mechanism, suggesting the possibility of an additional anticancer activity for mitoxantrone. Clin Cancer Res; 17(15); 5026-37. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 73%

Mitoxantrone Inhibits HIF-1α Expression in a Topoisomerase II–Independent Pathway

Toh

2011

Clinical Cancer Research

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“…In this study we used Novantrone (mitoxantrone dihydrochloride) (13)(14)(15)(16), which is a modem synthetic chemotherapeutic agent with a putative mode of action similar to that of the anthracycline antibiotic Adriamycin but which is considerably less toxic. Novantrone was selected on the basis of its activity in a wide range of experimental animal tumors and its inhibitory effects on both proliferating and nonproliferating tTo whom reprint requests should be addressed.…”

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confidence: 99%

Combination of a long-acting delivery system for luteinizing hormone-releasing hormone agonist with Novantrone chemotherapy: increased efficacy in the rat prostate cancer model.

Schally¹,

Kook²,

Monje³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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“…This is another new agent, related to the anthracyclines but thought to cause less cardiotoxicity. It is a DNA and RNA intercalating agent but may act through nonintercalative electrostatic interactions (21). A complete remission rate of 63% has been observed with mitozantrone (at 12 mg/mZ for 5 days) when combined with intermediate dose Ara-C (14).…”

Section: -A M S a (4'-( 9 Acridinylamino Methanesulfon-m-anisidide)mentioning

confidence: 99%

Therapeutic Progress–review Xxvi Drug Therapy for the Acute Leukaemias

1987

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Molecular and biochemical pharmacology of mitoxantrone

Cited by 109 publications

References 10 publications

Mitoxantrone Inhibits HIF-1α Expression in a Topoisomerase II–Independent Pathway

Mitoxantrone Inhibits HIF-1α Expression in a Topoisomerase II–Independent Pathway

Combination of a long-acting delivery system for luteinizing hormone-releasing hormone agonist with Novantrone chemotherapy: increased efficacy in the rat prostate cancer model.

Therapeutic Progress–review Xxvi Drug Therapy for the Acute Leukaemias

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