Hypoxia-activated prodrug TH-302 decreased survival rate of canine lymphoma cells under hypoxic condition

Yamazaki, H.; Lai, Yu‐Chang; Tateno, Morihiro; Setoguchi, Asuka; Goto‐Koshino, Yuko; Endo, Yasuyuki; Nakaichi, Munekazu; Tsujimoto, Hajime; Miura, Naoki

doi:10.1371/journal.pone.0177305

Cited by 7 publications

(12 citation statements)

References 36 publications

(48 reference statements)

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“…[6][7][8][9] A randomised phase II trial showed that adding TH-302 to gemcitabine therapy improved progression-free survival compared with gemcitabine alone in patients with untreated advanced-stage pancreatic cancer 7 We have previously reported that hypoxia enhances the growth potential of canine B-cell lymphoma cells by activating the HIF-1α signalling pathway; Evo decreased cellular survival rate under hypoxic conditions. 5 Our findings can contribute to the development of Evo-based hypoxia-targeting therapy for B-cell lymphoma in dogs.…”

mentioning

confidence: 78%

“…Hypoxic stimulation effectively improves growth potential and invasiveness of cancer cells in response to upregulation of the HIF-1α targeted genes. 2,5 One report suggested that HIF-1α may regulate expression levels of O( 6)-methylguanine-DNA methyltransferase (MGMT), which develop resistance to an alkylating agent, and HIF-1α knockdown can decrease MGMT expression. 20 Therefore, the HIF-1α signalling pathway may contribute to the malignant progression and chemoresistance of canine ITL.…”

Section: Discussionmentioning

confidence: 99%

“…targeted genes, which advance cancer progression, angiogenesis, cell survival and cell invasion. 2,5 Hypoxia reportedly induces evofosfamide (Evo) to release the DNA-alkylating moiety within hypoxic tumour regions; this indicates that Evo can serve as a hypoxia-targeting drug in human cancers, including those with leukaemia, pancreatic cancer, or soft-tissue sarcoma. [6][7][8][9] A randomised phase II trial showed that adding TH-302 to gemcitabine therapy improved progression-free survival compared with gemcitabine alone in patients with untreated advanced-stage pancreatic cancer 7 We have previously reported that hypoxia enhances the growth potential of canine B-cell lymphoma cells by activating the HIF-1α signalling pathway; Evo decreased cellular survival rate under hypoxic conditions.…”

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confidence: 99%

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Hypoxia‐targeting therapy for intestinal T‐cell lymphoma in dogs: Preclinical study using 3D in vitro models

Yamazaki

Tanaka²,

Nishida

et al. 2022

Vet Comparative Oncology

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The transcription factor hypoxia‐inducible factor 1α (HIF‐1α) is activated in response to oxygen deficiency, and is expressed in several cancers under intratumoral hypoxic stress that arises during pathogenic processes. Hypoxic stimulation enhanced the growth potential of canine lymphoma cells by activating the HIF‐1α signalling pathway in a previously reported study. The aim of this study was to establish a molecular design strategy for a novel hypoxia‐targeting therapy for intestinal T‐cell lymphoma (ITL) in dogs. We assessed the relationship between immunohistochemistry‐based HIF‐1α expression and clinical information, including signalment, tumour area, clinical signs, systemic diseases, treatment protocol, follow‐up information, chemotherapy response and overall survivals (OS), using 48 tissue samples from dogs with ITL. We investigated the effects of hypoxic stimulation on the biological behaviour of cell lines from three different types of canine ITL. We assessed the effects of evofosfamide (Evo; hypoxia‐activated prodrug) on cell lines cultured under hypoxic conditions. Our data showed that treatment response and overall survival might be significantly decreased in dogs with higher HIF‐1α expression than in those with lower HIF‐1α expression. Hypoxic culture (1% O2, 72 h) enhanced the invasiveness of cell lines and decreased their sensitivity to CCNU, resulting in hypoxia‐dependent aggressive behaviour. Sensitivity to Evo significantly increased in cell lines cultured under hypoxia compared with those cultured under normoxia, which exhibited hypoxia‐dependent apoptosis. Additionally, Evo downregulated HIF‐1α expression in cell lines cultured under hypoxia, suggesting that Evo might inhibit cell growth by inactivating HIF‐1α‐dependent cell signalling. Our results revealed the preclinical antitumor activity of Evo and provide a rationale for treatment strategies for dogs with ITL.

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confidence: 78%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Hypoxia‐targeting therapy for intestinal T‐cell lymphoma in dogs: Preclinical study using 3D in vitro models

Yamazaki

Tanaka²,

Nishida

et al. 2022

Vet Comparative Oncology

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“…40 TH-302 could suppress canine lymphoma survival by downregulating HIF-1α and its downstream genes. 41 Triggering Br-IPM release from TH-302 was accompanied by enhanced cytotoxicity when pO 2 was ,76 mmHg, according to electron paramagnetic resonance monitoring. 42 Nonpharmacological methods could exacerbate tumor hypoxia and therefore increase the in vitro and in vivo TH-302 cytotoxicity in pancreatic tumors.…”

Section: Nitroaromatics/nitroimidazolementioning

confidence: 96%

Hypoxia-activated prodrugs and redox-responsive nanocarriers

Ma¹,

Zhan²,

Xu³

et al. 2018

IJN

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Hypoxia is one of the marked features of malignant tumors, which is associated with several adaptation changes in the microenvironment of tumor cells. Therefore, targeting tumor hypoxia is a research hotspot for cancer therapy. In this review, we summarize the developing chemotherapeutic drugs for targeting hypoxia, including quinones, nitroaromatic/nitroimidazole, N-oxides, and transition metal complexes. In addition, redox-responsive bonds, such as nitroimidazole groups, azogroups, and disulfide bonds, are frequently used in drug delivery systems for targeting the redox environment of tumors. Both hypoxia-activated prodrugs and redox-responsive drug delivery nanocarriers have significant effects on targeting tumor hypoxia for cancer therapy. Hypoxia-activated prodrugs are commonly used in clinical trials with favorable prospects, while redox-responsive nanocarriers are currently at the experimental stage.

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“…Evofosfamide (also known as TH302), a hypoxiaactivated prodrug, has shown the ability to selectively kill cells by DNA damage in hypoxic tissues and significantly reduce the volume of tumors, especially tumors with massive hypoxic regions. Furthermore, TH302 can spread into peripheral normoxic regions once activated, which is called the bystander effect [41][42][43][44][45].…”

Section: Open Accessmentioning

confidence: 99%

Chitosan oligosaccharide decorated liposomes combined with TH302 for photodynamic therapy in triple negative breast cancer

Ding

Yang

et al. 2021

J Nanobiotechnol

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Background Triple negative breast cancer (TNBC) is an aggressive tumor with extremely high mortality that results from its lack of effective therapeutic targets. As an adhesion molecule related to tumorigenesis and tumor metastasis, cluster of differentiation-44 (also known as CD44) is overexpressed in TNBC. Moreover, CD44 can be effectively targeted by a specific hyaluronic acid analog, namely, chitosan oligosaccharide (CO). In this study, a CO-coated liposome was designed, with Photochlor (HPPH) as the 660 nm light mediated photosensitizer and evofosfamide (also known as TH302) as the hypoxia-activated prodrug. The obtained liposomes can help diagnose TNBC by fluorescence imaging and produce antitumor therapy by synergetic photodynamic therapy (PDT) and chemotherapy. Results Compared with the nontargeted liposomes, the targeted liposomes exhibited good biocompatibility and targeting capability in vitro; in vivo, the targeted liposomes exhibited much better fluorescence imaging capability. Additionally, liposomes loaded with HPPH and TH302 showed significantly better antitumor effects than the other monotherapy groups both in vitro and in vivo. Conclusion The impressive synergistic antitumor effects, together with the superior fluorescence imaging capability, good biocompatibility and minor side effects confers the liposomes with potential for future translational research in the diagnosis and CD44-overexpressing cancer therapy, especially TNBC. Graphic abstract

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Hypoxia-activated prodrug TH-302 decreased survival rate of canine lymphoma cells under hypoxic condition

Cited by 7 publications

References 36 publications

Hypoxia‐targeting therapy for intestinal T‐cell lymphoma in dogs: Preclinical study using 3D in vitro models

Hypoxia‐targeting therapy for intestinal T‐cell lymphoma in dogs: Preclinical study using 3D in vitro models

Hypoxia-activated prodrugs and redox-responsive nanocarriers

Chitosan oligosaccharide decorated liposomes combined with TH302 for photodynamic therapy in triple negative breast cancer

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