Dietary energy balance modulates ovarian cancer progression and metastasis

A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.     

Metformin intake is associated with better survival in ovarian cancer

BACKGROUND:

The objective of this case‐control study was to identify any association of metformin intake with the survival of patients with ovarian cancer.

METHODS:

In this retrospective case‐control study, women with ovarian cancer who received metformin (cases) were compared with women with ovarian cancer who did not receive metformin (controls). A 2‐layered analysis was conducted. In preliminary analysis, all cases (the OC cohort) were compared with controls at a 1:2 ratio. Subsequently, in definitive analysis, only patients who had epithelial ovarian cancer (the EOC cohort) were compared with controls at a 1:3 ratio. In the EOC cohort, cases were matched with controls for age (±5 years), International Federation of Gynecology and Obstetrics stage, and residual disease. Prognostic variables and disease specific survival were compared using chi‐square tests, the Kaplan‐Meier (log‐rank) method, and Cox proportional hazards analysis.

RESULTS:

In a preliminary analysis of the OC cohort (72 cases and 143 controls), cases had better survival (5‐year disease‐specific survival for cases vs controls, 73% vs 44%; P = .0002). In the definitive analysis of the EOC cohort (61 cases and 178 controls), the distribution of age, disease stage, optimal cytoreduction, serous histology, and platinum chemotherapy remained similar between cases and controls (P > .05). Despite these similarities, cases had significantly better survival (5‐year disease‐specific survival for cases vs controls, 67% vs 47%; P = .007). On multivariate analysis, metformin remained an independent predictor of survival (hazard ratio, 2.2; 95% confidence interval, 1.2‐3.8; P = .007) after controlling for disease stage, grade, histology, chemotherapy, body mass index, and surgical cytoreduction.

CONCLUSIONS:

The results of this study indicated an association of metformin intake with survival in patients with ovarian cancer. The receipt of metformin was associated with better survival, and the authors concluded that metformin is worthy of clinical trials in ovarian cancer. Cancer 2013. © 2012 American Cancer Society.     

The effects of graded levels of calorie restriction: I. impact of short term calorie and protein restriction on body composition in the C57BL/6 mouse

Faced with reduced levels of food, animals must adjust to the consequences of the shortfall in energy. We explored how C57BL/6 mice withdrew energy from different body tissues during three months of food restriction at graded levels up to 40% (calorie restriction: CR). We compared this to the response to equivalent levels of protein restriction (PR) without a shortfall in calories. Under CR there was a dynamic change in body mass over 30 days and thereafter it stabilized. The time to reach stability was independent of the level of restriction. At the end of three months whole body dissections revealed differential utilization of the different tissues. Adipose tissue depots were the most significantly utilized tissue, and provided 55.8 to 60.9% of the total released energy. In comparison, reductions in the sizes of structural tissues contributed between 29.8 and 38.7% of the energy. The balance was made up by relatively small changes in the vital organs. The components of the alimentary tract grew slightly under restriction, particularly the stomach, and this was associated with a parallel increase in assimilation efficiency of the food (averaging 1.73%). None of the changes under CR were recapitulated by equivalent levels of PR.     

Metformin suppresses azoxymethane‐induced colorectal aberrant crypt foci by activating AMP‐activated protein kinase

Metformin is widely used for the treatment of diabetes mellitus. Adenosine monophosphate‐activated protein kinase (AMPK) is known to be activated by metformin and to inhibit the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the protein translational machinery and cell proliferation. We examined the effect of metformin on the suppression of colorectal carcinogenesis in chemical carcinogen‐induced models. Seven‐wk‐old BALB/c mice were intraperitoneally (i.p.) injected with azoxymethane (AOM, 10 mg/kg) and then treated with or without metformin (250 mg/kg/d) for 6 wk (for the investigation of aberrant crypt foci [ACF] formation) or 32 wk (for polyp formation). We next investigated colonic epithelial proliferation using bromodeoxyuridine (BrdU) and the proliferating cell nuclear antigen (PCNA) labeling indices. Furthermore, to examine the indirect effect of metformin, the insulin resistance status and the serum lipid levels were assessed. Treatment with metformin significantly reduced ACF formation. The effect of metformin on colon polyp inhibition was relatively modest. No significant difference in body weight or glucose concentration was observed. The BrdU and PCNA indices decreased in mice treated with metformin. A Western blot analysis revealed that the phosphorylated mTOR, S6 kinase, and S6 protein levels in the colonic mucosa decreased significantly in mice treated with metformin. In conclusion, metformin suppresses colonic epithelial proliferation via the inhibition of the mTOR pathway through the activation of AMPK. As metformin is already used daily as an antidiabetic drug, it might be a safe and promising candidate for the chemoprevention of colorectal cancer. © 2010 Wiley‐Liss, Inc.     

The effects of graded levels of calorie restriction: III. Impact of short term calorie and protein restriction on mean daily body temperature and torpor use in the C57BL/6 mouse

A commonly observed response in mammals to calorie restriction (CR) is reduced body temperature (T_b). We explored how the T_b of male C57BL/6 mice responded to graded CR (10 to 40%), compared to the response to equivalent levels of protein restriction (PR) over 3 months. Under CR there was a dynamic change in daily T_b over the first 30–35 days, which stabilized thereafter until day 70 after which a further decline was noted. The time to reach stability was dependent on restriction level. Body mass negatively correlated with T_b under ad libitum feeding and positively correlated under CR. The average T_b over the last 20 days was significantly related to the levels of body fat, structural tissue, leptin and insulin-like growth factor-1. Some mice, particularly those under higher levels of CR, showed periods of daily torpor later in the restriction period. None of the changes in T_b under CR were recapitulated by equivalent levels of PR. We conclude that changes in T_b under CR are a response only to the shortfall in calorie intake. The linear relationship between average T_b and the level of restriction supports the idea that T_b changes are an integral aspect of the lifespan effect.     

Cancer prevention by adult‐onset calorie restriction after infant exposure to ionizing radiation in B6C3F1 male mice

Children are especially sensitive to ionizing radiation and chemical carcinogens, and limiting their cancer risk is of great public concern. Calorie restriction (CR) is a potent intervention for suppressing cancer. However, CR is generally not appropriate for children. This study, therefore, examined to see if adult‐onset CR influences the lifetime cancer risk in mice after early‐life exposure to ionizing radiation. Infant male mice (1‐week‐old) were exposed to 3.8 Gy X‐rays, fed a control 95 kcal/week or CR 65 kcal/week diet from 7 weeks of age (adult stage), and their lifespan and tumor development were assessed. Irrespective of CR, X‐rays shortened lifespan by 38%, and irrespective of irradiation CR extended lifespan by 20%. Thymic lymphoma (TL) and early‐occurring non‐TL were induced by radiation. The liver and Harderian gland were more susceptible to radiation‐induced tumors than the lungs and non‐thymic lymphoid tissues (late occurring). CR reduced the risk of hepatocellular carcinoma, late‐occurring non‐TL, lung tumor, Harderian tumor, and hemangioma but had less impact on TL and early‐occurring non‐TL. Most notably, the effects of X‐rays on induction of lung tumors, late‐occurring non‐TL and hemangioma were essentially canceled by CR. The ability of CR to prevent late‐occurring tumors was the same for non‐irradiated and irradiated mice, indicating that the mechanism by which CR influences cancer is independent of irradiation. Our results indicate that adult‐onset CR significantly inhibits late‐occurring tumors in a tissue‐dependent manner regardless of infant radiation exposure.     

Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer

Purpose: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer.Experimental Design: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models.Results: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet.Conclusions: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.     

Metformin suppresses breast cancer growth via inhibition of cyclooxygenase-2

Pre-clinical and on-going trials have indicated the advantage of using metformin as an anticancer drug alone or in combination with other chemotherapeutics for the treatment of patients with breast cancer. However, the mechanisms by which metformin attenuates tumorigenesis remain to be further elucidated. The present study investigated the anticancer effects of metformin in breast cancer and identified potential molecular targets of metformin using western blotting and immunohistochemical analysis. Metformin significantly decreased tumor cell proliferation in vitro and suppressed tumor growth in vivo. Moreover, it induced the activation of AMP-induced protein kinase and suppression of phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1), a downstream effector of the mTOR signaling pathway, and decreased cyclin D1 levels in in vitro and in vivo experimental models. Additionally, metformin inhibited cyclooxygenase (COX)-2 expression. Clinically, high expression levels of COX-2 and p-4E-BP1 in tissues of patients with breast cancer were significantly associated with enhanced lymphatic metastasis and distant metastasis. Thus, the current data suggested that metformin may have potential value as a synergistic therapy targeting both the COX-2 and mTOR signaling pathways.     

The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels,glucose homeostasis and oxidative stress in male C57BL/6 mice

Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-α and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR.     

Metformin: multi-faceted protection against cancer

The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics.     

AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell

Recent studies demonstrated that metformin exerts anti-neoplastic effect in a spectrum of malignancies. However, the mechanism whereby metformin affects various cancers, including gastric cancer, is poorly elucidated. Considering apoptosis plays critical role in tumorigenesis, we, in the present study, investigated the in vitro apoptotic effect of metformin on human gastric cancer cell and the underlying mechanism. Three differently-differentiated gastric cancer cell lines, MKN-28, SGC-7901 and BGC-823, along with one noncancerous gastric cell line GES-1 were used. We found that metformin treatment selectively induces apoptosis in the 3 cancer cell lines, but not the noncancerous one, as confirmed by flow cytometry, Caspase-Glo assay and western blotting against PARP and cleaved caspase 3. Moreover, the apoptotic effect of metformin seems to correlate negatively with the differentiation degree of gastric cancer. Metformin-induced apoptosis may be partially mediated through inhibition of anti-apoptotic survivin. Additionally, AMPK and mTOR, 2 important regulatory molecules responsible for metformin action, were investigated for their possible involvements in metformin-induced apoptosis of gastric cancer cell. AMPK knockdown by siRNA restores metformin-inhibited survivin expression and partially abolishes metformin-induced apoptosis. Similarly, forced overexpression of mTOR downstream effector p70S6K1 relieves metformin-induced inhibition of survivin and partly attenuates metformin-induced apoptosis. More importantly, survivin overexpression alleviates metformin-induced apoptosis. Xenograft nude mouse experiment also confirmed that AMPK/mTOR-mediated decrease of suvivin is in vivo implicated in metformin-induced apoptosis. Taken together, these evidences suggest that AMPK/mTOR-mediated inhibition of survivin may partly contribute to metformin-induced apoptosis of gastric cancer cell.     

Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages

Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKα1 activation in macrophage and silencing of AMPKα1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKα1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer.     

Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer

Increasing interest in repurposing the diabetic medication metformin for cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of hyperglycemia on metformin response and to address the applicability of metformin as a cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of metformin were required to inhibit cell viability, while metformin treatment in hyperglycemic conditions resulted in increased glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of hyperglycemia or via gene amplification facilitated metabolic escape from the effects of metformin. In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in metformin-treated hyperglycemic mice. These findings indicate that hyperglycemia inhibits the anti-cancer effects of metformin in vitro and in vivo. Furthermore, our results suggest that metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes.     

二甲双胍通过AMPK/Smad3信号通路抑制卵巢癌腹腔间皮细胞的间皮-间质转化

目的:探讨二甲双胍对人腹腔间皮细胞（human peritoneal mesothelial cells,HPMC）间皮-间质转化的影响及其可能机制,以及进一步对卵巢癌细胞系SKOV3系膜清除能力的影响。方法:搜集2018年02月至2021年02月襄阳市第一人民医院妇产科正常网膜组织和高级别浆液性卵巢癌网膜转移灶标本进行免疫组织化学检测Calretinin表达情况;分离、培养原代人腹腔间皮细胞并进行Calretinin流式鉴定;Western blot和Transwell实验检测二甲双胍或肿瘤上清处理正常患者来源HPMC后其间皮-间质转化相关蛋白（E-cadherin、Vimentin、α-SMA）及迁移能力改变情况;Western blot检测二甲双胍、Smad3抑制剂及AMPK干扰处理前后正常来源原代人腹腔间皮细胞中MMP2、E-cadherin、Vimentin、p-AMPK和p-Smad3的表达情况;SKOV3球体的系膜清除实验验证二甲双胍预处理人腹膜间皮细胞系HMrSV5对SKOV3系膜清除能力的影响。结果:正常网膜中Calretinin表达于腹腔侧表面的腹腔内皮细胞,卵巢癌网膜转移灶表面Calretinin表达缺失,肿瘤间质中高表达Calretinin;分离培养的肿瘤来源原代人腹腔间皮细胞流式检测表现为CD326-CD45-CD31-Calretinin+;二甲双胍能够抑制肿瘤上清诱导的正常来源原代HPMC的间皮-间质转化及迁移;二甲双胍能够抑制肿瘤上清诱导的正常来源原代HPMC中Smad3/MMP2通路活化和E-cadherin表达,并依赖于AMPK信号活化;二甲双胍预处理HMrSV5通过AMPK信号的介导抑制了HMrSV5的间皮-间质转化进而间接抑制了SKOV3的系膜清除能力。结论:卵巢癌转移灶中的间质成分部分来源于腹腔间皮细胞,二甲双胍通过AMPK调控的Smad3信号通路抑制其间皮-间质转化,进而抑制卵巢癌肿瘤细胞的系膜清除。     

Metformin inhibited colitis and colitis-associated cancer (CAC) through protecting mitochondrial structures of colorectal epithelial cells in mice

Although a mountain of papers have showed that metformin plays a role in inhibiting cancers, but the mechanism underpinning this has not yet fully elucidated. Herein, we used AOM/DSS model, the clinicopathological features are similar to those found in humans, to investigate the effects of metformin as well as combination with 5-FU in the prevention of colitis and colitis associated cancer (CAC). Oral metformin significantly inhibited DSS-induced ulcerative colitis and AOM/DSS-induced CAC. Metformin also ameliorated 5-FU-induced colorectal gastrointestinal symptoms in mice. Metformin combination with 5-FU strongly inhibited colorectal cancer. Metformin reduced levels of the NFκB signaling components p-IKKα/β, p-NFκB, p-IκBα in colorectal mucosal cells. Transmission electron microscopy analysis suggested that the inhibition of metformin on colitis and CAC might associate with its biological activity of protecting mitochondrial structures of colorectal epithelial cells. Further analysis by Mito Tracker Red staining assay indicated that metformin prevented H₂O₂-induced mitochondrial fission correlated with a decrease of mitochondrial perimeter. In addition, metformin increased the level of NDUFA9, a Q-module subunit required for complex I assembly, in colorectal epithelial cells. These observations of metformin in the inhibition of colitis and CAC might associate with its activity of activating the LKB1/AMPK pathway in colorectal epithelial cells. In conclusion, metformin inhibited colitis and CAC through protecting the mitochondrial structures of colorectal epithelial cells.     

雷帕霉素增强卵巢癌细胞系对顺铂敏感性的机制研究

目的：研究雷帕霉素对卵巢癌细胞系顺铂敏感性的影响,以及PI3K/AKT/mTOR信号通路（简称mTOR信号通路）与卵巢癌细胞系顺铂耐药的相关性;初探雷帕霉素增强卵巢癌细胞系顺铂敏感性的分子机制。方法采用CCK-8法检测卵巢癌顺铂耐药细胞系SKOV3/DDP的耐药指数（resistance index,RI）、细胞增殖抑制率;采用克隆平板实验观察不同用药方案对卵巢癌顺铂非耐药细胞系及SKOV3细胞系两种细胞系克隆形成的影响;采用蛋白质印迹法（Western blot）检测两种细胞系的蛋白表达差异。结果①SKOV3/DDP细胞系的RI为6.10,属中度耐药。②在SKOV3细胞系中,顺铂联合雷帕霉素作用24 h、48 h后的细胞增殖抑制率明显高于单用顺铂组,差异有统计学意义（P＜0.01）,两组间的72 h细胞增殖抑制率无明显的统计学意义（P＞0.05）;顺铂联合雷帕霉素作用于SKOV3/DDP细胞系24 h、48 h、72 h后的细胞增殖抑制率均明显高于单用顺铂组,差异有统计学意义（P＜0.01）。③雷帕霉素联合顺铂作用于SKOV3细胞系4 h后,其克隆形成抑制率明显高于单用顺铂组,差异有统计学意义（P＜0.01）。④SKOV3/DDP细胞系比SKOV3细胞系p-mTOR、p-AKT的表达升高,而mTOR、AKT的表达则相似。⑤联合用药组比单用顺铂组的PARP断裂增加。⑥雷帕霉素作用SKOV3细胞系24 h ,BCL2表达下调,LC3B由LC3BⅠ向LC3BⅡ转化增加;在SKOV3/DDP细胞系中未发现这两种作用。结论①在体外培养条件下,雷帕霉素能增强SKOV3及SKOV3/DDP细胞系对顺铂的敏感性。②mTOR信号通路激活可能在卵巢癌细胞系顺铂耐药机制中起重要作用。③雷帕霉素增强SKOV3细胞系对顺铂敏感性的分子机制包括：增强顺铂所致的DNA断裂、下调抗凋亡蛋白BCL2及引起细胞自噬;雷帕霉素增强SKOV3/DDP对顺铂敏感性分子机制可能与增强顺铂所致的DNA断裂有关。     

熊果酸联合顺铂抑制卵巢癌生长的实验研究

目的:探讨熊果酸(UA)对卵巢癌细胞株SKOV3及卵巢癌皮下移植瘤生长的抑制作用并探讨其机制.方法:采用四甲基偶氮唑蓝(MTT)比色法,检测UA对SKOV3细胞的增殖抑制效应;建立卵巢癌皮下移植瘤模型,观察UA 对移植瘤的生长抑制作用;用免疫组化检测凋亡相关蛋白Bcl-2和Bax的表达.结果: UA对体外培养的SKOV3细胞生长具有抑制作用,与DDP联合应用使SKOV3细胞生长进一步受到抑制.体内实验表明:各治疗组肿瘤的生长明显受到抑制,而联合治疗组抗瘤作用进一步增强.UA能下调肿瘤细胞中Bcl-2蛋白的表达,同时明显提高肿瘤细胞中Bax蛋白的表达.结论:UA可明显抑制卵巢癌细胞生长,并诱导细胞凋亡,其主要机制与调节Bcl-2和Bax的蛋白表达有关.