Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, P.R. China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, P.R. China.
Cell Death Dis. 2023 May 9;14(5):316. doi: 10.1038/s41419-023-05833-w.
Extranodal NK/T-cell lymphoma (NKTL) is a rare and aggressive form of extranodal lymphoma with a poor prognosis. Currently, there are very limited treatment options for patients with advanced-stage disease or those with relapsed/recurrent disease. Here we show that Chiauranib, an orally small molecule inhibitor of select serine-threonine kinases (aurora B, VEGFRs, PDGFR, CSF1R, c-Kit), inhibited NKTL cell proliferation, induced cell cycle arrest, as well as suppressed the microvessel density in vitro and in vivo similar as in other types of cancer cells. Surprisingly, Chiauranib unfolded a new effect to induce apoptosis of NKTL cells by triggering AIF-dependent apoptosis other than the traditional cyt-c/caspase mitochondrial apoptosis pathway. The knockdown of AIF in vitro and in vivo dramatically blocked the efficacy of Chiauranib on NKTL. Mechanistically, the release of AIF from mitochondria is due to the upregulation of VDAC1 by the AKT-GSK3β pathway and activation of calcium-dependent m-calpain, which promotes the cleavage of VDAC1 and therefore permits the release of AIF. Notably, the low expression of Bax in both NKTL cells and patient tissues restrained the cyt-c release. It resulted in the inhibition of cyt-c/caspase mitochondrial pathway, suggesting that drugs targeting this traditional pathway may not be effective in NKTL. Furthermore, we found that L-asparaginase triggered CD95 (Fas/Apo-1)-caspase 8-caspase 3 apoptotic pathway in NKTL cells, and combination of Chiauranib and L-asparaginase exhibited a synergistic effect, suggesting a feasibility to combine these two drugs for effective treatment of NKTL. This study demonstrates Chiauranib's positive efficacy toward NKTL through the activation of the AIF-dependent apoptosis pathway for the first time. The novel and multi-targets of Chiauranib and the synergistic effect with L-asparaginase may provide a promising therapy for NKTL patients.
结外 NK/T 细胞淋巴瘤（NKTL）是一种罕见且侵袭性的结外淋巴瘤，预后不良。目前，对于晚期疾病或复发/难治性疾病患者，治疗选择非常有限。在这里，我们表明，Chiauranib 是一种选择性丝氨酸-苏氨酸激酶（极光激酶 B、VEGFR、PDGFR、CSF1R、c-Kit）的口服小分子抑制剂，可抑制 NKTL 细胞增殖，诱导细胞周期停滞，并抑制体外和体内的微血管密度，与其他类型的癌细胞相似。令人惊讶的是，Chiauranib 通过触发依赖 AIF 的凋亡而不是传统的细胞色素 c/caspase 线粒体凋亡途径，发挥了诱导 NKTL 细胞凋亡的新作用。体外和体内敲低 AIF 可显著阻断 Chiauranib 对 NKTL 的疗效。在机制上，AIF 从线粒体中的释放是由于 AKT-GSK3β 通路上调 VDAC1 并激活钙依赖性 m-calpain，从而促进 VDAC1 的切割，从而允许 AIF 的释放。值得注意的是，Bax 在 NKTL 细胞和患者组织中的低表达限制了细胞色素 c 的释放。它导致细胞色素 c/caspase 线粒体途径的抑制，表明针对该传统途径的药物在 NKTL 中可能无效。此外，我们发现 L-天冬酰胺酶在 NKTL 细胞中触发 CD95（Fas/Apo-1）-caspase 8-caspase 3 凋亡途径，并且 Chiauranib 和 L-天冬酰胺酶联合使用具有协同作用，表明联合使用这两种药物治疗 NKTL 的可行性。这项研究首次证明了 Chiauranib 通过激活依赖 AIF 的凋亡途径对 NKTL 具有积极疗效。Chiauranib 的新颖性和多靶点以及与 L-天冬酰胺酶的协同作用可能为 NKTL 患者提供有希望的治疗方法。
