Molecular mechanism of bitter melon juice efficacy against pancreatic cancer.

苦瓜汁抗胰腺癌的分子机制。

• 批准号: 9128577
• 负责人: Rajesh Agarwal
• 金额: $ 38.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128577
• 关键词: Adenocarcinoma; Adverse effects; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Asians; Automobile Driving; Biological Markers; CASP3 gene; Cancer Model; Cancer Patient; Cancer Relapse; Cancer cell line; Cell Culture Techniques; Cessation of life; Clinical Trials; Complex; Country; Data; Diagnosis; Disease; Dose; Electron Transport; Enzymes; Erinaceidae; Event; FRAP1 gene; Food; Generations; Glycolysis; Growth; Health; Health Benefit; Human; Incidence; Inhibition of Apoptosis; Juice; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Melons; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Molecular; Momordica charantia; Mus; Mutation; NOD/SCID mouse; Neoplasm Metastasis; Notch Signaling Pathway; Nude Mice; Nutrient; Oral; Outcome; Oxidative Phosphorylation; Pancreas; Pathway interactions; Population; Process; Property; Publishing; Reactive Oxygen Species; Reporting; Resistance; Role; Safety; Signal Transduction; Signaling Molecule; Small Interfering RNA; Staging; Stress; Survival Rate; Symptoms; Testing; Time; Toxic effect; Transgenic Mice; Vegetables; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; chemotherapy; diabetic; feeding; gemcitabine; glucose metabolism; glucose uptake; in vivo; inhibitor/antagonist; mTOR Signaling Pathway; member; metabolic rate; mitochondrial membrane; mortality; mouse model; notch protein; novel; pancreatic cancer cells; research study; response; self-renewal; smoothened signaling pathway; stem cell population; tumor; tumor metabolism; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Pancreatic cancer (PanC) is an aggressive disease; median life of PanC patients post-diagnosis is <6 months and overall 5-year survival rate is 3-5%. Gemcitabine is the frontline chemotherapy for PanC that effectively eliminates bulk PanC cells; however spares cancer stem cell (CSC) population which causes cancer relapse as well as aggressiveness. Together, it is clear that additional strategies are urgently warranted to effectively lower PanC incidence, target CSC to control PanC relapse, and associated mortality. Noteworthy, PanC is a complex disease with multiple combinations of mutations, and therefore it is necessary to identify the agents with multiple targets to control both PanC growth and CSC-associated PanC relapse. Our published and preliminary studies show that bitter melon (Momordica charantia) juice (BMJ) significantly decreases the viability and induces strong apoptotic death of human PanC cell lines, which was associated with a robust AMPK activation, as both AMPK inhibitor and siRNA reversed BMJ-caused apoptosis. Furthermore, BMJ inhibited glycolysis and oxidative phosphorylation rate in PanC cells. Together these results suggested a 'metabolic shift' by BMJ in PanC cells. BMJ also strongly inhibited the sphere formation by PanC CSCs suggesting that it also targets CSC for its anti-PanC efficacy. Most notably, BMJ feeding by oral gavage at only 5mg dose/mouse/day resulted in 60% inhibition in MIA PaCa-2 xenograft growth in nude mice without any noticeable side effects or toxicity. Immunohistochemical analysis of xenografts showed that BMJ also inhibits proliferation and CSC biomarkers, induces apoptosis, and activates AMPK in vivo. Together, based on these and other findings, we hypothesize that BMJ causes metabolic shift in PanC cells through nutrient stress, AMPK activation and inhibiting signaling molecules related to metabolism and proliferation, which leads to strong growth inhibition and apoptosis specifically in PanC cells. Additionally, BMJ targets Notch/ Hedgehog signaling to effectively eliminate PanC CSC population; resulting in strong activity against PanC. The specific aims proposed are: I) To further define the mechanisms by which BMJ targets metabolism and affects AMPK-mediated growth inhibition and apoptosis in PanC cells; II) To further define the mechanisms by which BMJ targets Notch and Hedgehog pathways and effectively inhibits CSC population in PanC; and III) To further establish BMJ molecular mechanisms defined in specific aims I and II in PDX1-Cre; LSL-KRASG12D transgenic mouse model. It is important to highlight here that bitter melon is widely consumed as vegetable as well as juice especially in Asian countries; and has been attributed with multiple health beneficial properties such as anti-diabetic, anti-inflammatory, etc. Most notably, bitter melon has been tested in several clinical trials for its anti-diabetic effects and has plenty of human safety data. We, therefore, anticipate that the positive outcomes from the proposed studies will provide compelling rationale for initiating clinical trials to establish BMJ activity against human pancreatic cancer.

描述（由申请人提供）：胰腺癌（PANC）是一种侵略性疾病；诊断后panc患者的中位寿命小于6个月，总5年生存率为3-5％。吉西他滨是有效消除大量panc细胞的panc的前线化学疗法。但是，助长了癌症干细胞（CSC）群体，这会导致癌症复发和攻击性。很明显，迫切需要采取其他策略，以有效地降低panc的发生率，靶向CSC来控制panc复发和相关的死亡率。值得注意的是，PANC是一种复杂的疾病，具有多种突变组合，因此有必要识别具有多个靶标的药物以控制PANC生长和与CSC相关的panc复发。我们发表的初步研究表明，苦瓜（Momordica Charantia）果汁（BMJ）显着降低了生存能力，并诱发了人类panc细胞系的强烈凋亡死亡，这与强大的AMPK激活相关，因为AMPK抑制剂和SiRNA反向BMJ抑制的BMJ抑制作用。此外，BMJ抑制了panc细胞中的糖酵解和氧化磷酸化速率。这些结果一起表明BMJ在panc细胞中的“代谢转移”。 BMJ还通过PANC CSC强烈抑制球体的形成，这也表明它还针对CSC的抗panc疗效。最值得注意的是，仅以5mg剂量/小鼠/天进行口服饲料的BMJ喂食导致MIA PACA-2异种移植物在裸鼠中的抑制作用60％，而没有任何明显的副作用或毒性。异种移植物的免疫组织化学分析表明，BMJ还抑制增殖和CSC生物标志物，诱导凋亡并在体内激活AMPK。基于这些和其他发现，我们假设BMJ通过营养应激，AMPK激活并抑制与代谢和增殖有关的信号分子，导致pMJ的代谢转移，从而导致强烈的生长抑制和凋亡在panc细胞中特异性地抑制和凋亡。此外，BMJ靶向Notch/ Hedgehog信号传导可有效消除PANC CSC种群。导致对pan的强大活动。提出的具体目的是：i）进一步定义BMJ靶向代谢并影响AMPK介导的生长抑制和凋亡的机制； ii）进一步定义了BMJ靶向Notch和HedgeHog途径的机制，并有效抑制panc中的CSC人群； iii）进一步建立了在PDX1-CRE中特定目的I和II中定义的BMJ分子机制； LSL-KRASG12D转基因小鼠模型。重要的是要在这里强调，苦瓜被广泛食用为蔬菜以及果汁，尤其是在亚洲国家。并归因于多种健康有益的特性，例如抗糖尿病，抗炎等。最值得注意的是，苦瓜具有 在几项临床试验中对其抗糖尿病作用进行了测试，并具有大量的人体安全 数据。因此，我们预计拟议的研究的积极结果将为启动临床试验以建立针对人类胰腺癌的BMJ活性提供令人信服的理由。