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

Abstract

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.

Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

“…In accordance with in vitro observations [26] anthraquinone treatment of allergic mice reduced HIF-1α and VEGF expression along with reduced levels of p-AKT and active PIP 3 in the lungs (Figure 5A to D). …”

“…Recently topoisomerase 2-independent effects of mitoxantrone have also been described that may be of relevance for therapeutically modulating the aberrant immune response observed in asthma and RV-induced exacerbations. Specifically, mitoxantrone inhibited hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) expression through dephosphorylation of AKT in transformed cell lines suggesting that mitoxantrone regulates the phosphoinositide-3-kinase (PI3K)/AKT pathway [26]. …”

Cancer cell spheroids as a model to evaluate chemotherapy protocols

“…The enhancement of doxorubicin accumulation by mitoxantrone might be due to the inhibition of Hypoxia Inducible Factor 1α (HIF-1α) by this drug. 39 Indeed, HIF-1α silencing decreased the resistance to cisplatin and doxorubicin in the non-small cell lung cancer in vitro. 40 Finally, the additive reduction in cell viability observed after the incubation with doxorubicin and mitoxantrone could be due to a synergistic action of these drugs on DNA intercalation and unwinding.…”

“…40 Finally, the additive reduction in cell viability observed after the incubation with doxorubicin and mitoxantrone could be due to a synergistic action of these drugs on DNA intercalation and unwinding. 39 Recently, mitoxantrone was reported to inhibit the activity of cancer-associated kinases, focal adhesion kinase (FAK) among them. 41 Interestingly, FAK silencing in colon carcinoma spheroids sensitized them to 5-fluorouracil suggesting an indirect doxorubicin potentiation by mitoxantrone.…”

Surface PEGylation of Mesoporous Silica Nanorods (MSNR): Effect on loading, release, and delivery of mitoxantrone in hypoxic cancer cells

“…Hypoxic tumors are usually associated with elevated production of hypoxia-inducible factor (HIF-1), which plays an important role in the development of multidrug resistance. MTX has been shown to inhibit preferentially HIF-1α under hypoxic conditions 41 . MTX could successfully inhibit HIF-1α expression and accumulation in hypoxic tumors.…”