Zhong Li-Xia, Wu Mo-Li, Li Hong, Liu Jia, Lin Li-Zhu
Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510407, Guangdong, People's Republic of China.
Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, People's Republic of China.
Cancer Manag Res. 2019 Jul 4;11:6113-6124. doi: 10.2147/CMAR.S206301. eCollection 2019.
Resveratrol (Res) inhibits ovarian cancer (OC) cell growth but its in vivo anti-OC effects are unclear due to the low bioavailability of systemically administered Res. Intraperitoneal administration may overcome this therapeutic dilemma because it makes Res directly affect the abdominal tumors. Ethanol and DMSO are common Res solvents, while their reliability and safety for long-term in vivo treatment remain unknown.
A rat orthotopic OC model was established using the rat NUTU-19 OC cell line. Res dissolved in 10% ethanol or 0.2% DMSO was injected intraperitoneally (20 mg/kg/day) into tumor-free and tumor-bearing rats for 2 weeks. The tumors were collected for gross, morphological and molecular examinations, and blood and ascitic samples were obtained for a CA125 ELISA. Res concentration in ovarian tissues was determined by high performance liquid chromatography (HPLC).
The average tumor weight (0.187±0.065 g) of the Res-in-DMSO group was lower than that of untreated (0.426±0.091 g; <0.01) and Res-in-ethanol (0.238±0.073 g; <0.05) group. The average bloody ascitic volumes collected from untreated, Res-in-ethanol, and Res-in-DMSO groups were 5.65±0.27, 2.75±0.14, and 2.09±0.11 ml, respectively. Abundant TUNEL-positive cells, ARHI and PIAS3 upregulation, CA125 reduction, and decreased STAT3 nuclear translocation were found in the Res-in-ethanol and, especially, the Res-in-DMSO group. Widespread plaques of Res deposits were found on the abdominal serosa of the Res-in-ethanol group, but not in the Res-in-DMSO group. HPLC revealed a higher Res concentration in Res-in-DMSO-treated tumor tissues than in those treated by Res-in-ethanol (<0.01). Fertility was maintained after long-term Res treatment.
Intraperitoneal administration of Res effectively inhibited rat orthotopic ovarian cancer growth without affecting normal tissues. The Res-in-DMSO group had the highest drug bioavailability and therefore stronger tumor-suppressive effects on ovarian cancer tissues.
白藜芦醇（Res）可抑制卵巢癌（OC）细胞生长，但由于全身给药时Res的生物利用度较低，其体内抗OC作用尚不清楚。腹腔给药可能会克服这一治疗难题，因为它可使Res直接作用于腹部肿瘤。乙醇和二甲基亚砜（DMSO）是常用的Res溶剂，但其长期体内治疗的可靠性和安全性仍不明确。
使用大鼠NUTU-19 OC细胞系建立大鼠原位OC模型。将溶解于10%乙醇或0.2% DMSO中的Res腹腔注射（20 mg/kg/天）至无瘤和荷瘤大鼠体内，持续2周。收集肿瘤进行大体、形态学和分子检查，并采集血液和腹水样本进行CA125酶联免疫吸附测定（ELISA）。通过高效液相色谱法（HPLC）测定卵巢组织中的Res浓度。
Res-DMSO组的平均肿瘤重量（0.187±0.065 g）低于未治疗组（0.426±0.091 g；<0.01）和Res-乙醇组（0.238±0.073 g；<0.05）。从未治疗组、Res-乙醇组和Res-DMSO组收集的平均血性腹水量分别为5.65±0.27、2.75±0.14和2.09±0.11 ml。在Res-乙醇组，尤其是Res-DMSO组中发现大量TUNEL阳性细胞、ARHI和PIAS3上调、CA125降低以及STAT3核转位减少。在Res-乙醇组的腹部浆膜上发现广泛的Res沉积斑，但在Res-DMSO组中未发现。HPLC显示，Res-DMSO处理的肿瘤组织中的Res浓度高于Res-乙醇处理的肿瘤组织（<0.01）。长期Res治疗后生育能力得以维持。
腹腔注射Res可有效抑制大鼠原位卵巢癌生长，且不影响正常组织。Res-DMSO组的药物生物利用度最高，因此对卵巢癌组织的抑瘤作用更强。
