Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes.
Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes.
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DOI：
10.1073/pnas.1802184115
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发表时间：
2018-06-12
影响因子：
11.1
通讯作者：
Mochly-Rosen D
中科院分区：
文献类型：
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作者：
Saiki JP;Cao H;Van Wassenhove LD;Viswanathan V;Bloomstein J;Nambiar DK;Mattingly AJ;Jiang D;Chen CH;Stevens MC;Simmons AL;Park HS;von Eyben R;Kool ET;Sirjani D;Knox SM;Le QT;Mochly-Rosen D
头颈部癌症的放射治疗通常会导致口干，这是一种影响说话、吞咽和其他与生活质量有关的功能的衰弱状态。由于放射后唾液功能的恢复在很大程度上取决于存活的唾液干/祖细胞（SSPCs）的数量，我们认为保护SSPCs免受损伤对缓解口干至关重要。辐射后，SSPCs积累有毒醛，破坏DNA、蛋白质和脂质，导致细胞死亡。在这里，我们确定d-柠檬烯是醛脱氢酶3A1 （ALDH3A1）的活化剂，具有良好的安全性，可用于临床应用。ALDH3A1激活可减少SSPCs中醛的积累，增加球体形成能力，减少细胞凋亡，并在不降低抗癌作用的情况下保留放射后唾液腺的结构和功能。口干是头颈癌患者放射治疗最常见的副作用，会导致说话和吞咽困难。由于醛脱氢酶3A1 （ALDH3A1）在小鼠唾液干/祖细胞（SSPCs）中高度表达，我们试图通过基因功能丧失和药理学功能获得研究来确定ALDH3A1在SSPCs中的作用。使用DarkZone染料测量细胞内醛，我们观察到与野生型腺体相比，辐照的Aldh3a1−/−成年小鼠唾液腺细胞和富含SSPCs的整个小鼠胚胎唾液腺的原位醛积累更高。为了确定一种安全的ALDH3A1激活剂用于潜在的临床试验，我们筛选了一个中药文库，并分离出常用的食品调味剂d-柠檬烯作为单一组分激活剂。d-柠檬烯激活ALDH3A1可显著降低SSPCs和全胚腺中醛的积累，增加成球能力，减少细胞凋亡，改善体内颌下腺结构和功能。一项针对唾液腺肿瘤患者的0期研究显示，每日口服给药后，d-柠檬烯能有效地进入人唾液腺。鉴于其安全性和生物利用度，d-柠檬烯可能是缓解头颈癌放疗患者口干症的良好临床候选者。
Radiation therapy for head and neck cancer often leads to dry mouth, a debilitating condition that affects speaking, swallowing, and other functions related to quality of life. Since salivary functional recovery after radiation is largely dependent on the number of surviving salivary stem/progenitor cells (SSPCs), we reasoned that protection of SSPCs from injury is critical for mitigating dry mouth. Following radiation, SSPCs accumulate toxic aldehydes that damage DNA, proteins, and lipids, leading to cell death. Here, we identified d-limonene as an activator of aldehyde dehydrogenase 3A1 (ALDH3A1) with a favorable safety profile for clinical use. ALDH3A1 activation decreases aldehyde accumulation in SSPCs, increases sphere-forming ability, reduces apoptosis, and preserves salivary gland structure and function following radiation without reducing the anticancer effects. Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1−/− adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy.
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DOI：
10.1158/1940-6207.capr-12-0452
发表时间：
2013-06
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Miller JA;Lang JE;Ley M;Nagle R;Hsu CH;Thompson PA;Cordova C;Waer A;Chow HH
通讯作者：
Chow HH
DOI：
10.1158/1078-0432.ccr-11-0179
发表时间：
2011-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Banh A;Xiao N;Cao H;Chen CH;Kuo P;Krakow T;Bavan B;Khong B;Yao M;Ha C;Kaplan MJ;Sirjani D;Jensen K;Kong CS;Mochly-Rosen D;Koong AC;Le QT
通讯作者：
Le QT
干细胞移植在辐照腺体中的干细胞移植后拯救唾液腺功能。
影响因子：
3.7
作者：
Lombaert, Isabelle M. A.;Brunsting, Jeanette F.;Wierenga, Pieter K.;Faber, Hette;Stokman, Monique A.;Kok, Tineke;Visser, Willy H.;Kampinga, Harm H.;de Haan, Gerald;Coppes, Robert P.
通讯作者：
Coppes, Robert P.
DOI：
10.1016/j.ijrobp.2004.12.051
发表时间：
2005-07-15
影响因子：
7
作者：
Konings, AWT;Coppes, RP;Vissink, A
通讯作者：
Vissink, A
影响因子：
16.8
作者：
通讯作者：
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