Obrador Elena, Salvador-Palmer Rosario, Jihad-Jebbar Ali, López-Blanch Rafael, Dellinger Thanh H, Dellinger Ryan W, Estrela José M
Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 15 Av. Blasco Ibañez, 46010 Valencia, Spain.
Department of Surgery, Division of Gynecologic Surgery, City of Hope, 1500 East Duarte Rd, Duarte, CA 91010, USA.
Antioxidants (Basel). 2021 Mar 21;10(3):492. doi: 10.3390/antiox10030492.
Natural polyphenols are organic chemicals which contain phenol units in their structures and possess antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PT) is a phytoalexin originally isolated from the heartwood of red sandalwood. As recently reported by our group, PT was shown to be effective in the treatment of melanoma. Counterintuitively, PT is not effective (cytotoxic) against melanoma in vitro, and only under in vivo conditions does PT display its anticancer activity. This study elucidated that PT can be effective against melanoma through the inhibition of adrenocorticotropic hormone production in the brain of a mouse, which weakens the Nrf2-dependent antioxidant defenses of melanoma and also pancreatic cancers. This results in both the inhibition of tumor growth and sensitization of the tumor to oxidative stress. Moreover, PT can promote cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 content, a known stabilizer of lysosomal membranes. In addition, the safety of PT administered i.v. has been evaluated in mice. PT was found to be pharmacologically safe because it showed no organ-specific or systemic toxicity (including tissue histopathologic examination and regular hematology and clinical chemistry data) even when administered i.v. at a high dose (30 mg/kg per day × 23 days). Moreover, new pharmacological advances are being developed to increase its bioavailability and, thereby, its bioefficacy. Therefore, although applications of PT in cancer therapy are just beginning to be explored, it represents a potential (and effective) adjuvant/sensitizing therapy which may improve the results of various oncotherapies. The aim of this review is to present and discuss the results that in our opinion best support the usefulness of PT in cancer therapy, making special emphasis on the in vivo evidence.
天然多酚是一类在其结构中含有酚单元且具有抗肿瘤特性的有机化学物质。然而，一个关键问题是它们在体内条件下的半衰期短且生物利用度低。紫檀芪（3,5 - 二甲氧基 - 4'- 羟基芪；PT）是一种最初从紫檀木心材中分离出来的植物抗毒素。正如我们小组最近报道的那样，PT 被证明对黑色素瘤的治疗有效。与直觉相反，PT 在体外对黑色素瘤无效（无细胞毒性），只有在体内条件下 PT 才会显示出其抗癌活性。本研究阐明，PT 可以通过抑制小鼠大脑中促肾上腺皮质激素的产生来有效对抗黑色素瘤，这会削弱黑色素瘤以及胰腺癌中 Nrf2 依赖的抗氧化防御。这导致肿瘤生长受到抑制，并且肿瘤对氧化应激敏感。此外，PT 可以通过一种涉及溶酶体膜通透性增加的机制促进癌细胞死亡。根据不同癌细胞中溶酶体热休克蛋白 70 的含量（一种已知的溶酶体膜稳定剂），观察到不同等级的敏感性。此外，已经在小鼠中评估了静脉注射 PT 的安全性。发现 PT 在药理上是安全的，因为即使以高剂量（每天 30 mg/kg×23 天）静脉注射，它也没有显示出器官特异性或全身毒性（包括组织组织病理学检查以及常规血液学和临床化学数据）。此外，正在开发新的药理学进展以提高其生物利用度，从而提高其生物功效。因此，尽管 PT 在癌症治疗中的应用才刚刚开始探索，但它代表了一种潜在的（且有效的）辅助/增敏疗法，可能会改善各种肿瘤治疗的效果。这篇综述的目的是呈现并讨论我们认为最能支持 PT 在癌症治疗中有用性的结果，特别强调体内证据。
