Isopentenyl pyrophosphate secreted from Zoledronate-stimulated myeloma cells, activates the chemotaxis of γδT cells

Ashihara, Eishi; Munaka, Tatsuya; Kimura, Shinya; Nakagawa, Saori; Nakagawa, Yoko; Kanai, Masaki; Hirai, Hideyo; Abe, Hiromasa; Miida, Takashi; Yamato, Susumu; Shoji, Shuichi; Maekawa, Taira

doi:10.1016/j.bbrc.2015.05.118

Cited by 18 publications

(21 citation statements)

References 24 publications

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“…Common short-term side effects associated with Zol include “flu-like” symptoms (caused by activation of γδ T cells) [42, 43], hypocalcaemia [44], and renal failure [45]. Table S5 summarizes the hematologic toxicity, nephrotoxicity and hepatotoxicity parameters, and the plasma calcium level recorded for the healthy tumor-free CD1 mice 4 days after tail-vein i.v.…”

Section: Resultsmentioning

confidence: 99%

“…The key toxicity parameters recorded after i.v. administration of small molecule and encapsulated Zol were within the documented normal ranges for healthy CD1 mice except that the monocyte level of the CD1 mice administered with small-molecule Zol was above the normal range due to the activation of γδ T cells [43]. Although the biodistribution study revealed that the majority of the administered CaZol nMOFs were accumulated in the liver and kidney of healthy tumor-free mice, a therapeutic dose of CaZol nMOFs showed insignificant hepatotoxicity and nephrotoxicity in healthy CD1 mice.…”

Section: Resultsmentioning

confidence: 99%

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Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

et al. 2016

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Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of a novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80 to 85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

et al. 2016

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“…A biochemical basis for bisphosphonates as farnesyl pyrophosphate synthase inhibitors and disruptors of the mevalonate pathway with the resultant accumulation of isopentyl pyrophosphate is being elucidated (van Beek et al , ; Russell, ). Excess isopentyl pyrophosphate modulates osteoclast signaling (Russell, ) and gamma‐delta T‐cell activity (Sanders et al , ; Ashihara et al , ). Bisphosphonates bound to bone also affect the adjacent tissue in vitro through the induction of soluble mediators (Cornish et al , ).…”

Section: Anti‐resorptive Medication‐associated Osteonecrosis Of the Jawmentioning

confidence: 99%

“…Macrophages in vitro exhibit a decreased survival and adherence after bisphosphonate treatment (Hoefert et al , ) and an increased sensitivity to lipopolysaccharide‐induced apoptosis (Muratsu et al , ). These drugs exert actions on both the innate and adaptive immune systems, as T‐cell function is also altered by bisphosphonates (Sanders et al , ; Kikuiri et al , ; Ashihara et al , ; Park et al , ).…”

Section: Anti‐resorptive Medication‐associated Osteonecrosis Of the Jawmentioning

confidence: 99%

Hyperbaric oxygen therapy and osteonecrosis

et al. 2016

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Osteonecrosis of the jaw may be caused by radiation, medication, or infection. Optimal therapy requires a multimodal approach that combines surgery with adjuvant treatments. This review focuses on the use of adjunctive hyperbaric oxygen therapy for this condition. In addition to evidence regarding the basic and clinical science behind hyperbaric oxygen therapy, controversies in the field and economic implications are discussed. Oral Diseases (2017) 23, 141-151

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“…Injecting Vγ9Vδ2 T cells without additional treatment failed to demonstrate tumor-infiltrating cells and failed to reduce tumor volume. Treating myeloma patients with zoledronic acid increased Vγ9Vδ2 T cell migration into the tumor and infiltration depended on IPP secretion ( 96 ). An earlier study on mouse Vγ9Vδ2 T cell migration into murine tumors used antibody blocking to show a requirement for T cell receptor in chemotaxis and tumor infiltration ( 91 ).…”

Section: Preclinical and Clinical Studies Of Vγ9vδ2 T Cell Therapymentioning

confidence: 99%

Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local

Pauza¹,

Liou²,

Lahusen³

et al. 2018

Front. Immunol.

101

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Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vγ9Vδ2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models. Translating these findings to the clinic produced promising initial results but greater potency is needed. Here, we review the literature on gamma delta T cells in cancer therapy with emphasis on the Vγ9Vδ2 T cell subset. Our goal was to examine obstacles preventing effective Vγ9Vδ2 T cell therapy and strategies for overcoming them. We focus on the potential for local activation of Vγ9Vδ2 T cells within the tumor environment to increase potency and achieve objective responses during cancer therapy. The gamma delta T cells and especially the Vγ9Vδ2 T cell subset, have the potential to overcome many problems in cancer therapy especially for tumors with no known treatment, lacking tumor-specific antigens for targeting by antibodies and CAR-T, or unresponsive to immune checkpoint inhibitors. Translation of amazing work from many laboratories studying gamma delta T cells is needed to fulfill the promise of effective and safe cancer immunotherapy.

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Isopentenyl pyrophosphate secreted from Zoledronate-stimulated myeloma cells, activates the chemotaxis of γδT cells

Cited by 18 publications

References 24 publications

Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic

Hyperbaric oxygen therapy and osteonecrosis

Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local

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