Mode of Action of the Amaryllidaceae Alkaloid Lycorine-Promising Anticancer Agent

石蒜科生物碱石蒜碱的作用方式有前途的抗癌剂

• 批准号: 8763979
• 负责人: ALEXANDER KORNIENKO
• 金额: $ 47.55万
• 依托单位: TEXAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8763979
• 关键词: Actins; Alkaloids; Alkynes; Amaryllidaceae Alkaloids; Antineoplastic Agents; Apoptosis; Apoptotic; Avidin; Back; Binding; Binding Proteins; Biological; Biological Assay; Biological Factors; Biology; Biotin; Brain; Brain Neoplasms; Cancer Patient; Cancer cell line; Cell Line; Chemicals; Computers; Cytoskeleton; Data; Development; Dose; Evaluation; Exhibits; Foundations; Future; Glioblastoma; Glioma; Goals; Induction of Apoptosis; Investigation; Knowledge; Malignant Neoplasms; Melanoma Cell; Modeling; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Outcome; Pharmaceutical Preparations; Photoaffinity Labels; Preparation; Probability; Property; Proteins; Relative (related person); Research; Resistance; Site; Solid; Stimulus; Structure; Therapeutic; Time; Validation; Work; analog; base; cancer cell; cancer therapy; cancer type; design; drug discovery; experience; improved; in vivo; innovation; melanoma; migration; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; pharmacophore; public health relevance; treatment strategy; tumor

DESCRIPTION (provided by applicant): The ultimate goal of this project is the development of a novel therapeutic strategy for the treatment of cancer capitalizing on the unique antiproliferative effects of the alkaloid lycorine on apoptosis resistant cancers. Although a large majority of current cancer drugs exhibit their effects through the induction of apoptosis in tumor cells, many types of cancer, such as glioma, melanoma, NSCLC, among others, are resistant to proapoptotic stimuli and are typically associated with dismal prognoses. Therefore, new chemotypes that display antiproliferative effects against such apoptosis-resistant cancers and/or inhibit tumor metastatic spread are urgently needed. In preliminary work, the PI's collaborative chemical biology/drug discovery team has shown that the alkaloid lycorine modifies actin cytoskeleton organization in cancer cells, and impairs both their proliferation and migration. Lycorine exerts these effects with both apoptotic-resistant and susceptible cell lines, sensitizes cancer cells to proapoptotic agents, and displays 15 times greater potency toward cancer versus normal cells. Furthermore, lycorine showed significant therapeutic benefit in vivo in the B16F10 mouse melanoma model, consisting of orthotopically brain-grafted melanoma cells. These preliminary results form a compelling case for a thorough understanding of lycorine's mode of action in cancer cells and utilization of this knowledge for the development of novel strategies to treat cancers with dismal prognoses. The proposed work involves the preparation of lycorine- alkyne probes, which will be evaluated against a panel of apoptosis-resistant cancer cells with the goal of identifying derivatives retaining the antiproliferative potency and mode of action of lycorine. Suitable alkyne probes will then be used in protein pull-down assays, aimed at target protein identification. Several back-up target identification and target validation strategies are also proposed to confirm this innovative chemotherapeutic approach.

描述（由申请人提供）：该项目的最终目标是开发一种新型的治疗策略，用于治疗癌症，以利用生物碱番茄糖对抗细胞凋亡癌的独特抗增殖作用。虽然很大 当前大多数癌症药物通过诱导肿瘤细胞的凋亡而表现出其作用，肿瘤细胞中的许多类型的癌症，例如神经胶质瘤，黑色素瘤，NSCLC等，对促凋亡刺激具有抵抗力，通常与沮丧的预测有关。因此，迫切需要对这种抗凋亡癌和/或抑制肿瘤转移性扩散的新的化学型，这些化学型表现出抗增殖作用。在初步工作中，PI的合作化学生物学/药物发现团队表明，生物碱氨基氨酸修饰癌细胞中的肌动蛋白细胞骨架组织，并损害其增殖和迁移。番茄与凋亡耐药性和易感细胞系一起发挥这些作用，使癌细胞对促凋亡剂敏感，并显示出对癌症与正常细胞相对于正常细胞的效力的15倍。此外，在B16F10小鼠黑色素瘤模型中，氨核在体内显示出显着的治疗益处，由原位脑植血的黑色素瘤细胞组成。这些初步结果构成了一个令人信服的案例，可以透彻地了解番茄碱在癌细胞中的作用方式，并利用这种知识来开发新型策略，以惨淡的预后治疗癌症。提出的工作涉及番茄碱探针的制备，该探针将针对一组耐凋亡的癌细胞进行评估，其目的是鉴定衍生物保持抗增殖效力和番茄的作用方式。然后，合适的炔烃探针将用于针对靶蛋白鉴定的蛋白质下拉测定法。还提出了几种备用目标识别和目标验证策略，以确认这种创新的化学治疗方法。

项目成果

Novel Topologically Complex Scaffold Derived from Alkaloid Haemanthamine.

• DOI: 10.3390/molecules23020255
• 发表时间: 2018-01-28
• 期刊: Molecules (Basel, Switzerland)
• 作者: Govindaraju K;Masi M;Colin M;Mathieu V;Evidente A;Hudnall TW;Kornienko A
• 通讯作者: Kornienko A

Covalent modification of biological targets with natural products through Paal-Knorr pyrrole formation.

• DOI: 10.1039/c7np00024c
• 发表时间: 2017-08-30
• 期刊: Natural product reports
• 影响因子: 11.9
• 作者: Kornienko A;La Clair JJ
• 通讯作者: La Clair JJ

Higginsianins A and B, Two Diterpenoid α-Pyrones Produced by Colletotrichum higginsianum, with in Vitro Cytostatic Activity.

• DOI: 10.1021/acs.jnatprod.5b00779
• 发表时间: 2016-01-22
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Cimmino A;Mathieu V;Masi M;Baroncelli R;Boari A;Pescitelli G;Ferderin M;Lisy R;Evidente M;Tuzi A;Zonno MC;Kornienko A;Kiss R;Evidente A
• 通讯作者: Evidente A

Marine Mollusk-Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance.

• DOI: 10.1002/med.21423
• 发表时间: 2017-07
• 期刊: Medicinal research reviews
• 影响因子: 13.3
• 作者: Ciavatta ML;Lefranc F;Carbone M;Mollo E;Gavagnin M;Betancourt T;Dasari R;Kornienko A;Kiss R
• 通讯作者: Kiss R

Sesterterpenoids with Anticancer Activity.

• DOI: 10.2174/0929867322666150821101047
• 发表时间: 2015
• 期刊: Current medicinal chemistry
• 影响因子: 4.1
• 作者: Evidente A;Kornienko A;Lefranc F;Cimmino A;Dasari R;Evidente M;Mathieu V;Kiss R
• 通讯作者: Kiss R