Potentials of C‐C motif chemokine 2–C‐C chemokine receptor type 2 blockers including propagermanium as anticancer agents

Yumimoto, Kanae; Sugiyama, Shigeaki; Mimori, Koshi; Nakayama, Keiichi I.

doi:10.1111/cas.14075

Cited by 35 publications

(35 citation statements)

References 60 publications

(80 reference statements)

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“…In addition, PG also has therapeutic effects in other inflammatory disease such as atherosclerosis. 38 In our study, we first confirmed that PG plays a neuroprotective role in hemorrhagic stroke. The present results showed that PG significantly reduced the permeability of the BBB, relieved brain edema by increasing the protein expression of ZO-1 and inhibited the p38 MAPK signaling pathway.…”

Section: Discussionsupporting

confidence: 73%

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Guo

Lin

et al. 2019

FASEB j.

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Intracerebral hemorrhage (ICH) remains a devastating type of stroke that lacks an effective treatment. Recent evidence has demonstrated that CCL2 is involved in the blood‐brain barrier (BBB) disruption and propagermanium (PG) as a CCL2 receptor inhibitor is neuroprotective in ischemic stroke. However, whether PG therapy exert effective role in acute ICH still unclear. In this study, our goal was to investigate the potential role of CCL2 and the effects of PG in ICH. Differentially expressed RNAs including CCL2 were detected in human ICH. CCL2 and the activation of p‐p38 MAPK and AQP4 expression were analyzed in rats after ICH. Brain water content and BBB integrity as well as neurological function were also examined after PG administration. In addition, the mechanism by which CCL2‐mediated BBB injury was further investigated by cell coculture. Our findings showed that PG could effectively reduce brain edema and improve neurobehavioral functions. p‐p38 MAPK and AQP4 expression were significantly inhibited by PG in vivo and in vitro. To the best of our knowledge, this is the first demonstration of PG in neuroprotecting the BBB integrity by inhibition of CCL2‐CCR2‐p38 MAPK pathway following ICH, targeting CCL2 could be developed as a novel treatment for hemorrhagic stroke.

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Section: Discussionsupporting

confidence: 73%

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Guo

Lin

et al. 2019

FASEB j.

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“…Several clinical trials of CCL2 inhibitors have been undertaken for therapeutic intervention in solid malignancies . In a mouse model, Bonapace et al found that the interruption of treatment with anti‐CCL2 neutralizing Ab led to enhanced metastasis due to an influx of monocytes into the metastatic site and a rebound of IL‐6 levels .…”

Section: Discussionmentioning

confidence: 99%

“…Several clinical trials of CCL2 inhibitors have been undertaken for therapeutic intervention in solid malignancies. 8,9 In a mouse model, Bonapace et al found that the interruption of treatment with anti-CCL2 neutralizing Ab led to enhanced metastasis due to an influx of monocytes into the metastatic site and a rebound of IL-6 levels. 23 In conclusion, this study of PG as monotherapy in BC patients has shown a manageable safety profile and provides a basis for exploring the clinical use of PG as an antimetastatic drug for BC patients.…”

Section: Discussionmentioning

confidence: 99%

“…The C‐C motif chemokine 2 (CCL2, also known as monocyte chemoattractant protein‐1 [MCP‐1]) and the signaling pathway modulated by its receptor (CCR2) play a crucial role in the recruitment of monocytes to the sites of inflammation . Recently, the signaling pathway in the tumor microenvironment has generated increasing interest due to its association with tumor progression and metastasis, including that in BC . CCL2 is overexpressed in breast cancer tissues, and patients with high expression of CCL2 have early recurrence or poor prognosis in breast cancer .…”

Section: Introductionmentioning

confidence: 99%

“…5 Recently, the signaling pathway in the tumor microenvironment has generated increasing interest due to its association with tumor progression and metastasis, including that in BC. [6][7][8][9] CCL2 is overexpressed in breast cancer tissues, 10 and patients with high expression of CCL2 have early recurrence or poor prognosis in breast cancer. [11][12][13] We previously showed that increased expression of CCL2 due to downregulated expression of F-box and WD repeat domain containing 7 (FBXW7) in bone marrow-derived stromal host cells promoted the formation of premetastatic niches through recruitment of myelomonocytic cell-derived suppressor cells, thereby promoting metastatic tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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Phase I dose‐escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer

et al. 2020

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The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow‐derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid‐derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7‐deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose‐escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end‐point was the percentage of patients who experience dose‐limiting toxicity. Twelve patients were enrolled in the study. Dose‐limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)‐6, in agreement with our previous mouse model. Also, IL‐6 was downregulated in a PG dose‐dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494.

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Chemokines as possible therapeutic targets in metastatic melanoma

et al. 2023

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Background Cutaneous melanoma is a relentless form of cancer which continues to rise in incidence. Currently, cutaneous melanoma is the leading cause of skin cancer‐related mortality, which can mainly be attributed to its metastatic potential. The activation of chemokine axes is a major contributor to melanoma metastasis through its involvement in promoting tumour cell migration, proliferation, survival, and adhesion. This review will focus on the role of chemokines in melanoma and possible therapeutic strategies to alter chemokine activation and subsequently inhibit the activation of signalling cascades that may promote metastasis. Methods A literature review was conducted to evaluate chemokines as possible therapeutic targets in metastatic melanoma. Results The crosstalk between signalling pathways and immune responses in the melanoma microenvironment resembles a complex and dynamic system. Therefore, the involvement of governing chemokine axes in the promotion of cutaneous and metastatic melanoma demands a proper understanding of the tumour microenvironment in order to identify possible targets and develop appropriate treatments against melanoma. Conclusion Even though chemokine axes are regarded as promising therapeutic targets, it has become increasingly evident that chemokines can play a critical role in both tumour inhibition and promotion. The inhibition of chemokine axes to inhibit signalling cascades in target cells that regulate metastasis should, therefore, be carefully approached.

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Potentials of C‐C motif chemokine 2–C‐C chemokine receptor type 2 blockers including propagermanium as anticancer agents

Cited by 35 publications

References 60 publications

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Phase I dose‐escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer

Chemokines as possible therapeutic targets in metastatic melanoma

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