分子碘如何攻击乳腺癌?

（碘是身体必须的天然药物系列 3）

乳腺癌

研究人员已经阐明了分子碘的作用机制，以确定它是如何帮助保护女性免受纤维囊性乳房疾病(FBC)的影响，并证实它是如何攻击乳腺癌的。

许多研究之前都建议补充碘可以促进乳房健康，但是没有一个研究确切地确定了它是如何与FBC细胞一起工作的。调查人员试图确定使分子碘有效的特定的作用机理。

多年来,“尽管一些研究表明,分子碘可促进乳房健康和保护纤维囊性乳房疾病和潜在的癌症,没有人确定分子碘的作用机理在乳房纤维囊性的情况下,“Usha Nagavarapu说,博士研究项目的董事兼首席研究员。“临床前的调查证实了作用机理，并让医学界有理由重新研究早期的研究，寻找如何最好地使用分子碘治疗和保护女性的线索。”

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两项研究

研究人员进行了体外研究，以评估分子碘影响乳腺癌细胞和由纤维囊性乳腺组织衍生的细胞的生化作用。

FBC的研究使用了MCF10A，这是一种由36岁的女性白种人的纤维囊性乳腺组织衍生而来的人的乳腺上皮细胞系。用分子碘对其进行了不同剂量和增殖的测定。其次是关键重要标记物的基因表达分析，它们负责细胞的生长和凋亡。同样，从健康的女性捐赠者身上提取的原发性人类乳腺上皮细胞被用作内部控制。

乳腺癌研究的重点是两种常见的乳腺癌亚型，分别是乳腺癌细胞系MCF7 (a luminal a subtype)和MDA-MB231(三阴性亚型)。细胞在不同浓度下用分子碘处理，以测定细胞的增殖和细胞死亡。随后是基因表达分析的关键重要分子标记，主要负责细胞生长和细胞凋亡。从健康的女性捐赠者身上提取的原发性乳腺上皮细胞被用作内部控制。

研究发现

这些研究的数据表明，分子碘对乳腺癌和纤维囊性乳房疾病的细胞生长都有显著的抑制作用。数据还显示，在研究中使用的乳腺癌细胞系和从纤维囊性乳腺组织中提取的细胞中，细胞死亡的数量急剧增加。

在纤维囊性乳房疾病的研究中，使用定量RT-PCR的基因表达分析证实了控制G1-S期过渡的细胞周期基因是上调的。在Cyclin B的表达水平上没有明显的变化，这再次表明细胞在进入细胞分裂之前被逮捕。上调了核激素受体PPAR-和PPAR-的表达。BCL-2，细胞死亡抑制因子升高，caspase-3表达降低，提示分子碘可通过激活caspase-独立细胞凋亡诱导细胞死亡。

在乳腺癌细胞系研究中，使用定量RT-PCR的基因表达分析也证实了控制G1-S期过渡的细胞周期基因在很大程度上是上调的。在Cyclin B的表达水平上没有看到变化，这进一步表明细胞在进入细胞分裂之前被逮捕。BCL-2、PPAR-和PPAR-也随着caspase-3的下调而上调，表明通过激活caspase-独立的凋亡通路，分子碘诱导细胞死亡。有趣的是，在分子碘处理过程中发现了间充质-上皮转移或MET发生，这表明在侵入式MDA-MB231细胞中，GATA3和E-cadherin的急剧增加和vimentin的显著下调。

“我们的临床前研究使我们能够理解控制肿瘤细胞生长的机制，并证明了分子碘对乳腺癌细胞系的强大的细胞作用，”研究的研究员Zack Z. Xu说。“这些结果也证明了分子碘对调节乳腺癌EMT分化计划的良好效果，这是肿瘤发生和转移所必需的。”

目前正在进行进一步的研究，以确定分子碘在这些乳腺癌亚型中使用体外三维模型可能产生的影响。

“我们的临床前数据表明，分子碘的管理可能会增强传统的治疗乳腺癌和纤维囊性乳房疾病的疗法，”徐说。

参考文献

How Molecular Iodine Attacks Breast Cancer

Oncology Times: December 25th, 2016 - Volume 38 - Issue 24 - p 34

doi: 10.1097/01.COT.0000511599.52147.f1

News

Article Outline

breast cancer

breast cancer

Researchers have elucidated the mechanism of action for molecular iodine to determine how it helps protect women from fibrocystic breast condition (FBC) and confirm how it attacks breast cancer.

Numerous studies have previously suggested iodine supplementation can promote breast health, but none had determined precisely how it worked with FBC cells. Investigators sought to identify the specific MOA that made molecular iodine effective.

“Although several studies have, through the years, shown that molecular iodine can promote breast health and protect women from fibrocystic breast condition and potentially cancer, no one has ever identified molecular iodine's mechanism of action in fibrocystic breast condition,” said Usha Nagavarapu, PhD, study director and principal investigator of the project. “The pre-clinical investigations confirm the MOA and give the medical community reason to revisit the earlier research for clues on how best to use molecular iodine to treat and protect women.”

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Two Studies

Investigators conducted in vitro studies to assess the biochemical interaction through which molecular iodine affects breast cancer cells and cells derived from fibrocystic breast tissue.

The FBC study used MCF10A, a human immortalized mammary epithelial cell line derived from fibrocystic breast tissues of a 36-year-old female Caucasian. It was treated with molecular iodine at various doses and proliferation was measured. This was followed by gene expression analysis of key important markers, which are responsible for cell growth and apoptosis. Again, primary human mammary epithelial cells derived from a healthy female donor were used as an internal control.

The breast cancer study focused on two common breast cancer subtypes using well-established breast cancer cell lines, MCF7 (a luminal A subtype) and MDA-MB231 (a triple-negative subtype). Cells were treated with molecular iodine at various concentrations to measure proliferation and cell death. This was subsequently followed by gene expression analysis of key important molecular markers, which are primarily responsible for cell growth and apoptosis. Primary human mammary epithelial cells derived from a healthy female donor were used as an internal control.

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Research Findings

Data from these studies indicated that molecular iodine has potent inhibitory effects on cell growth in both breast cancer and FBC. The data also showed a dramatic increase in cell death in breast cancer cell lines used in the study and in cells derived from fibrocystic breast tissue.

In the FBC study, gene expression analysis using quantitative RT-PCR confirmed that cell cycle genes controlling G1-S phase transition were up-regulated. No significant changes were seen in Cyclin B expression levels which, again, suggests that cells were arrested before entry into cell division. Expression of nuclear hormone receptors PPAR-α and PPAR-γ was up-regulated. BCL-2, inhibitor of cell death was increased, while expression of caspase-3 was decreased, thereby suggesting molecular iodine can induce cell death through activation of caspase—independent apoptosis.

In the breast cancer cell line study, gene expression analysis using quantitative RT-PCR also confirmed that cell cycle genes controlling G1-S phase transition were largely up-regulated. Changes were not seen in Cyclin B expression levels, which further suggest that cells were arrested before entry into cell division. BCL-2, PPAR-α, and PPAR-γ was also up-regulated along with down-regulation of caspase-3 suggesting molecular iodine induced cell death through activation of caspase-independent apoptosis pathway. Interestingly, mesenchymal-epithelial transition or MET occurrence was noticed upon molecular iodine treatment as indicated by sharp increase of GATA3 and E-cadherin and significant down-regulation of vimentin in invasive MDA-MB231 cells.

“Our preclinical study enables us to understand the mechanism controlling tumor cells growth and demonstrates potent cellular effects of molecular iodine on breast cancer cell lines,” said Zack Z. Xu, investigator in the research. “These results also demonstrate promising effects of molecular iodine on regulating breast cancer EMT differentiation program that is required for tumor initiation and metastasis.”

Further studies are underway to determine possible effects of molecular iodine in these breast cancer subtypes using in vitro 3D models.

“Our preclinical data suggest that administration of molecular iodine may enhance traditional therapies for the treatment of breast cancer and FBC,” said Xu.

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Background on Iodine

While the application of iodine supplementation has long been recognized in clinics, treatment effects have not been effective because iodine supplements in the market are either unstable or contain iodine salts, both of which are proven to be ineffective and have strong, undesirable side effects. Only molecular iodine (I2) has been found consistently useful in the promotion of breast health. Regular use of molecular iodine has been shown to reduce the sensitivity of breast cells to the proliferative effects of estrogen, resulting in normalization of breast tissue.

The challenge with molecular iodine is that it is unstable and oxidizes, losing properties useful for breast health. Today, only one formulation of I2 that targets breast cells is commercially available. It consists of iodide and iodate salts that, when exposed to gastric pH, react to form molecular iodine.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

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