High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, People's Republic of China.
Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, People's Republic of China.
Clin Epigenetics. 2021 Feb 25;13(1):41. doi: 10.1186/s13148-021-01025-5.
Concurrent thoracic radiation plus chemotherapy is the mainstay of first-line treatment for limited-stage small cell lung cancer (LS-SCLC). Despite initial high responsiveness to combined chemo- and radiotherapy, SCLC almost invariably relapses and develops resistance within one year, leading to poor prognosis in patients with LS-SCLC. Developing new chemical agents that increase ionizing radiation's cytotoxicity against SCLC is urgently needed.
Dual histone deacetylase (HDAC) and PI3K inhibitor FK228 not only displayed potent anticancer activity, but also enhanced the therapeutic effects of radiotherapy in SCLC cells. Mechanistically, radioresistant SCLC cells exhibit a lower level of histone H3K9 acetylation and a higher expression level of the MRE11-RAD50-NBS1 (MRN) complex and show more efficient and redundant DNA damage repair capacities than radiosensitive SCLC cells. FK228 pretreatment resulted in marked induction of H3k9 acetylation, attenuated homologous recombination (HR) repair competency and impaired non-homologous end joining (NHEJ) repair efficacy, leading to the accumulation of radiation-induced DNA damage and radiosensitization.
The study uncovered that FK228 sensitized human radioresistant SCLC cells to radiation mainly through induction of chromatin decondensation and suppression of DNA damage signaling and repair. Our study provides a rational basis for a further clinical study to test the potential of FK228 as a radiosensitizing agent to increase the radiation-induced tumor cell kill in LS-SCLC patients.
同步胸部放疗加化疗是局限期小细胞肺癌(LS-SCLC)一线治疗的主要方法。尽管初始时对联合化疗和放疗有高度反应,但 SCLC 几乎总是在一年内复发并产生耐药性,导致 LS-SCLC 患者预后不良。开发新的化学药物来增加电离辐射对 SCLC 的细胞毒性作用是迫切需要的。
双重组蛋白去乙酰化酶(HDAC)和 PI3K 抑制剂 FK228 不仅显示出强大的抗癌活性,而且增强了 SCLC 细胞的放射治疗效果。从机制上讲,耐辐射的 SCLC 细胞表现出较低水平的组蛋白 H3K9 乙酰化和更高水平的 MRE11-RAD50-NBS1(MRN)复合物表达,并且表现出更有效和冗余的 DNA 损伤修复能力,比辐射敏感的 SCLC 细胞更强。FK228 预处理导致明显的 H3k9 乙酰化诱导,减弱同源重组(HR)修复能力并损害非同源末端连接(NHEJ)修复效果,导致辐射诱导的 DNA 损伤积累和放射增敏。
该研究揭示 FK228 主要通过诱导染色质去凝聚和抑制 DNA 损伤信号和修复来使人类耐辐射 SCLC 细胞对辐射敏感。我们的研究为进一步的临床研究提供了合理的依据,以测试 FK228 作为放射增敏剂的潜力,以增加 LS-SCLC 患者的辐射诱导肿瘤细胞杀伤。