Antifungal Therapy with Itraconazole Impairs the Anti-Lymphoma Effects of Rituximab by Inhibiting Recruitment of CD20 to Cell Surface Lipid Rafts

Ringshausen, Ingo; Feuerstacke, Yvonne; Krainz, Philipp; Hollander, Jürgen den; Hermann, Ken; Buck, Andreas K.; Peschel, Christian; Bueschenfelde, Christian Meyer zum

doi:10.1158/0008-5472.can-10-0259

Cited by 15 publications

(8 citation statements)

References 18 publications

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“…Currently, clinical trials aimed at establishing the use of ICZ in malignancies of the breast (NCT00798135), prostate (NCT00887458) and lung (NCT007769600) are underway. But as suggested by Ringshausen et al (36) and our studies, there are potential issues that need to be addressed before considering a widespread use of ICZ as a chemotherapeutic agent.…”

Section: Discussionmentioning

confidence: 72%

“…Moreover, ICZ has been recently reported to interfere with rituximab immunotherapy in patients suffering from B-cell lymphoma (36). In summary, we present evidence that the use of ICZ in vulnerable populations such as those immunosuppressed patients or those receiving targeted immunotherapy should be approached with caution and under strict surveillance to prevent detrimental side effects.…”

Section: Discussionmentioning

confidence: 99%

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Itraconazole, a Commonly Used Antifungal, Inhibits Fcγ Receptor–Mediated Phagocytosis

Niño

Cauvi

Maio

2014

Shock

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Itraconazole (ICZ)‡ is commonly used for the treatment of fungal infections, particularly in immunocompromised patients. In addition, ICZ has been recently found to have anti-angiogenic effects and is currently being tested as a new chemotherapeutic agent in several cancer clinical trials. We have previously shown that ICZ impaired complex N-linked glycosylation processing, leading to the accumulation of high-mannose glycoproteins on the surface of macrophages. This investigation was directed at determining the effects of ICZ on phagocytosis as a major function of macrophages. We found a significant decrease in the phagocytosis of opsonized bacterial particles in ICZ-treated murine macrophages in comparison with non-treated macrophages. Furthermore, the impairment of phagocytosis was associated with a decrease in cell surface expression of Fcγ receptors (FcγR) as well as alteration of their glycosylation pattern. Concomitantly, a reduction in all three isoforms of the FcγR family (i.e., Fcgr1, Fcgr2 and Fcgr3) mRNA levels was observed after incubation with ICZ. The effect of ICZ on phagocytosis and FcγR expression was reversed by addition of LDL. These studies indicate that ICZ treatment certainly has a dramatic effect on macrophage function, which could result in a potential impairment of the immune system's ability to respond to pathogens and may lead to elevated incidence of infections.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Itraconazole, a Commonly Used Antifungal, Inhibits Fcγ Receptor–Mediated Phagocytosis

Niño

Cauvi

Maio

2014

Shock

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“…Of these 13 publications, nine reported tumor regression or eradication 8 , 9 , 12 , 13 , 15 - 19 and four reported slowed, delayed, or arrested growth 7 , 10 , 11 , 14 . The four demonstrating arrested growth, employed passive antibody therapy (Rituximab), adjuvant therapy (IL-1 receptor agonist, TLR-2 agonist), or dendritic cell vaccination.…”

Section: Resultsmentioning

confidence: 99%

A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth

et al. 2012

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We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords “immunotherapy” AND “cancer” for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5–121 mm3 in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm3 was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm3, and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm3, and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth.

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“…44 Finally, conformational changes or altered reorganization of CD20 within lipid rafts can be associated with impaired binding and reduced antitumor activity of anti-CD20 mAbs. 9,45 All processes that cause CD20 downregulation could potentially impair antitumor activity of anti-CD20 mAbs and lead to resistance to rituximab. Here, we add another mechanism that seems to be of clinical significance, i.e., a drugmediated transcriptional downregulation of CD20 levels.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies

Winiarska

Bojarczuk

Pyrzyńska

et al. 2014

mAbs

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Clinical trials with SRC family kinases (SFKs) inhibitors used alone or in a combination with anti-CD20 monoclonal antibodies (mAbs) are currently underway in the treatment of B-cell tumors. However, molecular interactions between these therapeutics have not been studied so far. A transcriptional profiling of tumor cells incubated with SFKs inhibitors revealed strong downregulation of MS4A1 gene encoding CD20 antigen. In a panel of primary and established B-cell tumors we observed that SFKs inhibitors strongly affect CD20 expression at the transcriptional level, leading to inhibition of anti-CD20 mAbs binding and increased resistance of tumor cells to complement-dependent cytotoxicity. Activation of the AKT signaling pathway significantly protected cells from dasatinib-triggered CD20 downregulation. Additionally, SFKs inhibitors suppressed antibody-dependent cell-mediated cytotoxicity by direct inhibition of natural killer cells. Abrogation of antitumor activity of rituximab was also observed in vivo in a mouse model. Noteworthy, the effects of SFKs inhibitors on NK cell function are largely reversible. The results of our studies indicate that development of optimal combinations of novel treatment modalities with anti-CD20 mAbs should be preceded by detailed preclinical evaluation of their effects on target cells.

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Antifungal Therapy with Itraconazole Impairs the Anti-Lymphoma Effects of Rituximab by Inhibiting Recruitment of CD20 to Cell Surface Lipid Rafts

Cited by 15 publications

References 18 publications

Itraconazole, a Commonly Used Antifungal, Inhibits Fcγ Receptor–Mediated Phagocytosis

Itraconazole, a Commonly Used Antifungal, Inhibits Fcγ Receptor–Mediated Phagocytosis

A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth

Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies

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