Evaluation of Current and Upcoming Therapies in Oral Mucositis Prevention

Wu, Jerry; Beale, Keola K.; Joseph, D.

doi:10.2217/fon.10.133

Cited by 12 publications

(10 citation statements)

References 151 publications

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“…However, except for “guidelines” for symptom management, no well-established therapeutic strategies to treat chemotherapy-induced intestinal mucositis are available [10-12]. Thus the development of an effective intervention against chemotherapy-related mucositis has high priority in oncological supportive care [13,14]. …”

Section: Introductionmentioning

confidence: 99%

Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis

et al. 2014

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BackgroundRecent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis.MethodsMice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student’s t-test (paired two-tailed) and χ2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05.ResultsBLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR.ConclusionsBLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.

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Section: Introductionmentioning

confidence: 99%

Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis

et al. 2014

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“…Severe oral mucositis could require feeding tubes, management of severe pain, and prematurely halting radiotherapy 1 . Excessive inflammation and epithelial ablation are key features of oral mucositis 3,4 . Palifermin, a KGF (human keratinocyte growth factor) recombinant protein, is approved for preventing oral mucositis in bone-marrow transplant patients 1 .…”

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confidence: 99%

Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis

Han

Bian

et al. 2013

Nat Med

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We report that K5.Smad7 mice, which express Smad7 transgene by a keratin-5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to NF-κB activation known to contribute to oral mucositis, we found activated TGF-β signaling in oral mucositis. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor CtBP1 transcriptionally repressed Rac1, and Smad7 abrogated this repression. Knocking down Rac1 in mouse keratinocytes abrogated Smad7-induced migration. Topically applying Smad7 protein with a cell permeable Tat-tag (Tat-Smad7) to oral mucosa showed preventive and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified novel molecular mechanisms involved in oral mucositis pathogenesis and our data suggest an alternative therapeutic strategy to block multiple pathological processes of oral mucositis.

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“…Oral mucositis is characterized by an infiltration of excessive inflammatory cells, epithelial ablation, and ulcer development (Scully et al, 2006; Wu et al, 2010). Oral mucositis consists of five overlapping stages: initiation, damage response, signal amplification, ulceration, and healing.…”

Section: Pathological Processes Of Oral Mucositismentioning

confidence: 99%

The role of Smad7 in oral mucositis

et al. 2015

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Oral mucositis, a severe oral ulceration, is a common toxic effect of radio- or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. Among cancer patients, at least 40% and up to 70%, of individuals treated with standard chemotherapy regimens or upper-body radiation, develop oral mucositis. To date, there is no FDA approved drug to treat oral mucositis in cancer patients. The key challenges for oral mucositis treatment are to repair and protect ulcerated oral mucosa without promoting cancer cell growth. Oral mucositis is the result of complex, multifaceted pathobiology, involving a series of signaling pathways and a chain of interactions between the epithelium and submucosa. Among those pathways and interactions, the activation of nuclear factor-kappa B (NF-κB) is critical to the inflammation process of oral mucositis. We recently found that activation of TGFβ (transforming growth factor β) signaling is associated with the development of oral mucositis. Smad7, the negative regulator of TGFβ signaling, inhibits both NF-κB and TGFβ activation and thus plays a pivotal role in the prevention and treatment of oral mucositis by attenuating growth inhibition, apoptosis, and inflammation while promoting epithelial migration. The major objective of this review is to evaluate the known functions of Smad7, with a particular focus on its molecular mechanisms and its function in blocking multiple pathological processes in oral mucositis.

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Evaluation of Current and Upcoming Therapies in Oral Mucositis Prevention

Cited by 12 publications

References 151 publications

Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis

Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis

Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis

The role of Smad7 in oral mucositis

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