PO.ET05.02 · 实验与分子治疗
Imipridone类药物ONC201、ONC206和ONC212对小细胞肺癌细胞系表现出强效杀伤和集落阻滞
Imipridones ONC201, ONC206, and ONC212 show potent killing and colony arrest of small-cell lung cancer cell lines
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：小细胞肺癌（SCLC）约占所有肺癌的15%，估计5年生存率仅为7%。虽然大多数SCLC病例最初对化疗有反应，但多数（70-80%）病例会复发并对一线治疗产生耐药。因此，进一步研究新型治疗药物极为必要。Imipridone类药物是一类选择性抗癌药物，通过激活整合应激反应并增加TRAIL表达来导致癌细胞死亡。虽然ONC201（dordaviprone）已在小细胞及其他多种癌症中被研究，但其衍生物ONC206和ONC212尚未在SCLC中得到探索。因此，本研究在SCLC背景下比较了ONC201、ONC206和ONC212。
方法：使用了三种SCLC细胞系：H526、H1048、H1882。在活力测定中，将细胞以1000个/孔接种于96孔板中，处理前允许其过夜贴壁。在imipridone处理72小时后，通过Cell-TiterGlo®测定评估活力，以得出每种药物的IC50。在各细胞系中，于用每种imipridone进行等毒性处理（IC25、IC50、IC75）后的24小时、48小时和72小时进行Western blot（WB）。还对两种细胞系（H1048、H1882）在用每种药物的等毒性剂量处理三天后接续十四天无药孵育后，一式三份进行了集落形成实验（CFA）。
结果：在各细胞系中，ONC212表现出最低的IC50，其次是ONC206和ONC201。通过WB，ATF4、cPARP和ClpX的变化因药物而异，其中ONC212通常诱导最早且最显著的表达变化。CFA显示，处理72小时后ONC212导致集落形成的下降最大，其次是ONC206，然后是ONC201。
结论：本研究结果提示，SCLC可能对imipridone类药物高度敏感，尤其是ONC212。未来的工作将旨在探索联合疗法及潜在机制，包括衰老诱导、可能导致增殖性阻滞的细胞周期改变、代谢变化以及生长和存活通路的改变，以进一步表征敏感性和集落阻滞表型。
查看英文原文 English abstract
Introduction: Small cell lung cancer (SCLC) represents about 15% of all lung cancers, with an estimated 5-year survival rate of only 7%. While most SCLC cases initially respond to chemotherapy, a majority (70-80%) of cases recur and become resistant to first-line treatments. As such, further investigation of novel therapeutics is heavily warranted. Imipridones are a class of selective anti-cancer drugs that activate integrated stress response and increase TRAIL expression to lead to cancer cell death. While ONC201 (dordaviprone) has been investigated in small-cell and various other cancers, its derivatives ONC206 and ONC212 have not yet been explored within SCLC. As such, the present study compares ONC201, ONC206, and ONC212 within the context of SCLC.
Methods: Three SCLC cell lines were used: H526, H1048, H1882. For viability assays, cells were plated at 1000 cells/well in a 96-well plate and allowed to adhere overnight before treatment. Viability was assessed 72h after imipridone treatment by Cell-TiterGlo® assay to yield each drug's IC50. Western Blots (WBs) were performed across cell lines at 24h, 48h, and 72h following equitoxic treatments with each imipridone (IC25, IC50, IC75). Colony formation assays (CFAs) were also performed in triplicate for two cell lines (H1048, H1882) after three-day treatment with equitoxic doses of each drug followed by fourteen days of drug-free incubation.
Results: Across cell lines, ONC212 exhibited the lowest IC50, followed by ONC206 and ONC201. By WB, changes in ATF4, cPARP, and ClpX differed by drug, with ONC212 generally inducing the earliest and most significant changes in expression. CFA showed that ONC212 resulted in the greatest decrease in colony formation after 72 hours of treatment, followed by ONC206 and then ONC201.
Conclusions: The present findings suggest that SCLC may be highly sensitive to imipridones, particularly ONC212. Future works will aim to explore combination therapies and potential mechanisms including senescence induction, cell cycle alterations that may lead to reproductive arrest, metabolic changes, and alterations in growth and survival pathways in order to further characterize sensitivity and the colony arrest phenotype.
利益披露 Disclosure
A. Y. Su, None..
C. Purcell, None..
S. Zhang, None..
L. Zhou, None..
A. S. Uruchurtu, None.
W. S. El-Deiry,
Jazz Pharmaceuticals/Oncoceutics/Chimerix Stock, Other, Wafik S. El-Deiry co-founded Oncoceutics, Inc., a subsidiary of Chimerix/Jazz Pharmaceuticals. Dr. El-Deiry has disclosed his relationship with Chimerix/Jazz Pharmaceuticals and potential conflict of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest..
p53-Therapeutics g., Board of Directors, non-salaried role), Other Business Ownership, Founder, shareholder (no research funding) in p53-Therapeutics, an early-stage company developing small molecules targeting mutant p53..
Caris Life Sciences g., Board of Directors, non-salaried role), Other, Co-chair of Caris Life Sciences, on the Executive Committee for Precision Oncology Alliance (Brown University is a member), no research funding..
Oncotarget g., Board of Directors, non-salaried role), Editor-in-Chief (uncompensated).
Ocean Biomedical g., Board of Directors, non-salaried role), Scientific Advisory Board (uncompensated).
Global Cancer Technology Other, Equity.
ACS BrightEdge g., Board of Directors, non-salaried role), Advisory board (uncompensated).
Resurrect Therapeutics g., Board of Directors, non-salaried role), Other Business Ownership, Founder, Shareholder.
WIN Consortium g., Board of Directors, non-salaried role), Chair (uncompensated).
SMURF-Therapeutics g., Board of Directors, non-salaried role), Founder, Shareholder (SRA) of early-stage company developing small molecules targeting hypoxia.