LTX-315 (K-K-W-W-K-K-W-Dip-K-NH2) is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis[1].
In vitro，The IC50 value for LTX-315 was 30μM after only 5 minutes of exposure and lowered to 17μM after 60 minutes on A375 melanoma cells, and treated cells displayed a rapid change from a normal epithelial morphology to a total collapse of the cells with an extrusion of cytoplasmic content [2]. LTX-315 (0-200μg/ml) dissipated the inner mitochondrial transmembrane potential (Δψm) of U2OS cells, but could not completely dissipate U2OS cells those stably expressing a TFAM-GFP fusion [3].
In vivo, LTX-315 strongly inhibited tumor growth in B16-bearing mice, but not in B16-bearing MyD88-/- mice [4]. LTX-315 (1mg peptide/injection; twice; i.t.) combined with liposomal doxorubicin (8mg/kg body weight; twice; i.t.) produced a significant additive antitumor effect, with 50% of animals achieving complete remission; it also enhanced tumor necrosis, increased CD4+/CD8+ cell infiltration, and prolonged survival in 4T1 mammary carcinomas mouse model [5].
References:
[1]. Zhou, Heng, et al. "The oncolytic peptide LTX-315 triggers immunogenic cell death." Cell death & disease 7.3 (2016): e2134-e2134.
[2]. Eike, Liv-Marie, et al. "The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells." Oncotarget 6.33 (2015): 34910.
[3]. Zhou, Heng, et al. "The oncolytic peptide LTX-315 kills cancer cells through Bax/Bak-regulated mitochondrial membrane permeabilization." Oncotarget 6.29 (2015): 26599.
[4]. Li, Xiao-Qing, et al. "LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells." Frontiers in Immunology 15 (2024): 1332922.
[5]. Camilio, Ketil A., et al. "Combining the oncolytic peptide LTX-315 with doxorubicin demonstrates therapeutic potential in a triple-negative breast cancer model." Breast Cancer Research 21.1 (2019): 9.
LTX-315 (K-K-W-W-K-K-W-Dip-K-NH2)是一种阳离子两亲性肽，它能快速使线粒体膜发生通透性改变，从而引发部分由BAX/BAK1控制、且不依赖于半胱天冬酶的细胞坏死[1]。
在体外实验中，在A375黑色素瘤细胞中，LTX-315的IC₅₀值在处理5分钟后为30μM，处理60分钟后降至17μM。并且处理后的细胞会迅速从正常的上皮形态转变为细胞完全崩解，并伴有细胞质内容物的外排[2]。LTX-315（0–200μg/mL）消除了U2OS细胞的线粒体内膜跨膜电位（Δψm），但对于稳定表达TFAM-GFP融合蛋白的U2OS细胞，无法完全消除其Δψm[3]。
在体内实验中，LTX-315可显著抑制B16荷瘤小鼠的肿瘤生长，但在B16荷瘤的MyD88-/-小鼠中则无明显作用[4]。在4T1乳腺癌小鼠模型中，LTX-315（1mg/次；瘤内注射；共2次）联合脂质体多柔比星（8mg/kg体重；共2次；瘤内注射）产生了显著的协同抗肿瘤作用，50%的动物达到完全缓解；同时增强了肿瘤坏死，增加了CD4+/CD8+细胞浸润，并延长了动物生存期[5]。