Protective effects of mangafodipir against chemotherapy-induced ovarian damage in mice.
Protective effects of mangafodipir against chemotherapy-induced ovarian damage in mice.
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DOI：
10.1186/s12958-018-0426-y
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发表时间：
2018-10-27
期刊：
影响因子：
--
通讯作者：
Kikkawa F
中科院分区：
文献类型：
--
作者：
Qin Y;Iwase A;Murase T;Bayasula;Ishida C;Kato N;Nakamura T;Osuka S;Takikawa S;Goto M;Kotani T;Kikkawa F
鉴于化疗导致女性癌症患者卵巢损伤的严重性，包括通过使用冷冻技术和药物保存生育能力，需要进行调查。此前的研究表明，卵巢损伤与抗癌药物引起的氧化应激有关。因此，超氧化物歧化酶(SOD)可能是药物保护卵巢的关键因素。本研究的目的是确定锰络合物和超氧化物歧化酶模拟物芒果地平对抗癌药物诱导的颗粒细胞凋亡和原始卵泡激活的抑制作用。用甲基三氯硅烷溶液和免疫印迹法检测体外培养的人非黄体化颗粒细胞系(HGrC)经过氧化氢(H_2O_2)、顺铂或紫杉醇处理后，同时加入芒果地平对caspase-3裂解的影响。用顺铂或紫杉醇处理6周龄雌性ICR小鼠，对卵巢各个发育阶段的卵泡进行计数和形态分析，并对caspase-3、Ki67和氧化应激标志物4-羟基壬烯醛进行免疫组织化学检测。此外，将芒果地平注射到接种ES-2的6周龄雌性BALB/c小鼠体内，以分析芒果地平是否抑制顺铂或紫杉醇的抗肿瘤作用。芒果地平在体外可减轻过氧化氢和抗癌药物诱导的细胞凋亡。Mangafodipir还可减少4-羟基壬烯醛的表达，并减少顺铂和紫杉醇诱导的颗粒细胞凋亡。此外，芒果地平还能抑制原始卵泡的丢失。小鼠肿瘤移植研究表明，芒果地平不影响抗癌药物的抗肿瘤作用。氧化应激可能是顺铂和紫杉醇诱导原始卵泡丢失的机制之一。芒果地平可部分通过其超氧化物歧化酶活性减少顺铂和紫杉醇诱导的颗粒细胞凋亡和原始卵泡的激活。同时，芒果地平可能还有其他潜在的机制来抑制原始卵泡的激活。此外，芒果地平可减轻顺铂和紫杉醇引起的卵巢损伤，但不影响它们的抗肿瘤活性。因此，尽管芒果地平的疗效可能有限，但它可能是在抗癌治疗期间保留生育能力的一种新选择。
Given the seriousness of chemotherapy-induced ovarian injury in female cancer patients, the preservation of fertility, including through the use of cryopreservation technology and pharmaceuticals, requires investigation. Previous studies have shown that damage to the ovaries is related to oxidative stress caused by anticancer drugs. Therefore, superoxide dismutase (SOD) may represent a key factor in the pharmacological protection of the ovaries. The aim of our study was to identify the effects of mangafodipir, a manganese chelate and SOD-mimetic, on suppression of apoptosis in granulosa cells and primordial follicle activation induced by anticancer drugs. Cell viability assays using methyltrichlorosilane solutions and immunoblotting for cleaved caspase-3 were performed in in vitro experiments with the simultaneous addition of mangafodipir to human non-luteinized granulosa cell line (HGrC) cultures treated with hydrogen peroxide (H2O2), cisplatin, or paclitaxel. Count and morphological analyses of follicles at each developing stage in the ovaries and immunohistochemistry for cleaved caspase-3, Ki67 and 4-hydroxynonenal, a marker for oxidative stress, were also performed using mangafodipir-injected 6-week-old female ICR mice treated with cisplatin or paclitaxel. Further, mangafodipir was injected into 6-week-old female BALB/c mice inoculated with ES-2 to analyze whether mangafodipir inhibits the anti-tumor effects of cisplatin or paclitaxel treatment. Mangafodipir attenuated apoptosis induced by H2O2 and anticancer drugs in vitro. Mangafodipir also decreased the expression of 4-hydroxynonenal and reduced cisplatin- and paclitaxel-induced apoptosis in granulosa cells in vivo. In addition, mangafodipir inhibited the loss of primordial follicles. Tumor xenograft studies in mice showed that mangafodipir did not affect anticancer drug antitumor effects. Oxidative stress might be one of the mechanisms of cisplatin- and paclitaxel-induced the loss of primordial follicles. Mangafodipir can reduce cisplatin- and paclitaxel-induced apoptosis in granulosa cells and primordial follicle activation partially via its SOD activity. At the same time, mangafodipir might have other potential mechanisms to inhibit the activation of primordial follicles. Further, mangafodipir attenuated the ovarian damage caused by cisplatin and paclitaxel without affecting their antitumor activities. Mangafodipir, therefore, though its efficacy might be limited, may be a new option for the preservation of fertility during anticancer treatment.
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DOI：
10.1186/1477-7827-10-49
发表时间：
2012-06-29
期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
--
作者：
Agarwal A;Aponte-Mellado A;Premkumar BJ;Shaman A;Gupta S
通讯作者：
Gupta S
影响因子：
15.9
作者：
Coriat, Romain;Alexandre, Jerome;Batteux, Frederic
通讯作者：
Batteux, Frederic
影响因子：
82.9
作者：
Gonfloni, Stefania;Di Tella, Lucia;Cesareni, Gianni
通讯作者：
Cesareni, Gianni
影响因子：
--
作者：
Ben-Aharon I;Levi M;Margel D;Yerushalmi R;Rizel S;Perry S;Sharon E;Hasky N;Abir R;Fisch B;Tobar A;Shalgi R;Stemmer SM
通讯作者：
Stemmer SM
影响因子：
--
作者：
Di Emidio G;Rossi G;Bonomo I;Alonso GL;Sferra R;Vetuschi A;Artini PG;Provenzani A;Falone S;Carta G;D'Alessandro AM;Amicarelli F;Tatone C
通讯作者：
Tatone C