Zoledronic Acid Is Effective against Experimental Malignant Pleural Effusion

Stathopoulos, Georgios T.; Moschos, Charalampos; Loutrari, Heleni; Kollintza, Androniki; Psallidas, Ioannis; Karabela, Sophia P.; Magkouta, Sophia; Zhou, Zongmin; Papiris, Spyros; Roussos, Charis; Kalomenidis, Ioannis

doi:10.1164/rccm.200710-1513oc

Cited by 47 publications

(87 citation statements)

References 47 publications

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“…Mice received 1 mg/kg intraperitoneal TRFK5, which provides prolonged bioactivity (37), in ''prevention'' (Days 0 and 8) and ''regression'' (Day 8) protocols, the latter aimed at therapy of established MPEs developing around Day 8 (13,38).…”

Section: Il-5 Neutralizationmentioning

confidence: 99%

“…Tissue sections were immunolabeled as described previously (13)(14)(15)38), or stained with Biebrich scarlet for eosinophils (39).…”

Section: Histologymentioning

confidence: 99%

“…The increased IL-5 concentration in MPE compared with serum suggests local production in the malignancy-affected pleural space ( Figure 1B). We subsequently sought to assess eosinophils and IL-5 in a mouse model of lung adenocarcinomainduced MPE (13)(14)(15)38). Pleural accumulation of eosinophils was observed 14 days after intrapleural injection of LLC cells into C57BL/6 mice ( Figure 1C).…”

Section: Eosinophils and Il-5 Are Present In Human And Mouse Mpementioning

confidence: 99%

“…For these studies, wild-type (C57BL/6 il5 1/1 ) mice received intrapleural LLC cells followed by 1 mg/kg intraperitoneal IgG2a (control) or anti-IL-5 antibody (TRFK5) in two protocols designated as prevention (Days 0 and 8 after LLC cells) or regression studies (Day 8 after LLC cells). This latter study design was aimed at unveiling potential therapeutic effects of TRFK5 against already established mouse MPE, which develop around Day 8 (13,38). Fourteen days after LLC cell injection, all mice developed MPE; however, TRFK5-treated mice in both prevention and regression studies displayed decreased MPE formation and intrapleural tumor growth compared with IgGtreated controls ( Figure 4B).…”

Section: Il-5 Neutralization Limits Experimental Mpementioning

confidence: 99%

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Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

Stathopoulos¹,

Sherrill²,

Karabela³

et al. 2010

Am J Respir Crit Care Med

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Rationale: IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE. Objectives: To determine the role of IL-5 in MPE formation. Methods: The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5 1/1 ) and IL-5-deficient (il5 2/2 ) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray. Measurements and Main Results: Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5 1/1 mice, il5 2/2 mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5 1/1 and il5 2/2 mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5 1/1 mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo. Conclusions: Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.

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Section: Il-5 Neutralizationmentioning

confidence: 99%

“…Tissue sections were immunolabeled as described previously (13)(14)(15)38), or stained with Biebrich scarlet for eosinophils (39).…”

Section: Histologymentioning

confidence: 99%

Section: Eosinophils and Il-5 Are Present In Human And Mouse Mpementioning

confidence: 99%

Section: Il-5 Neutralization Limits Experimental Mpementioning

confidence: 99%

See 2 more Smart Citations

Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

Stathopoulos¹,

Sherrill²,

Karabela³

et al. 2010

Am J Respir Crit Care Med

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“…The results of previous studies have shown that ZOL has anticancer activity against several human neoplasms such as leukemia, breast, prostate, and pancreatic cancers in vivo . 21, 22, 23, 24 The mechanism underlying these anti‐proliferative effects is thought to involve the inhibition of RAS GTPase prenylation 25, 26…”

mentioning

confidence: 99%

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Kato

Futamura

Kanematsu

et al. 2015

Intl Journal of Cancer

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Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild‐type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS‐MAPK and AKT‐mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status.

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Malignant Pleural Effusion

Marazioti¹,

Stathopoulos²

2013

Experimental Metastasis: Modeling and Analysis

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Zoledronic Acid Is Effective against Experimental Malignant Pleural Effusion

Abstract: ZA is effective against experimental MPE, suggesting that this intervention should be considered for testing in clinical trials.

Cited by 47 publications

References 47 publications

Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Malignant Pleural Effusion

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