Tubeimoside 1 Acts as a Chemotherapeutic Synergist via Stimulating Macropinocytosis.
Tubeimoside 1 Acts as a Chemotherapeutic Synergist via Stimulating Macropinocytosis.
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Tubeimoside 1 通过刺激巨胞饮作用作为化疗增效剂
DOI：
10.3389/fphar.2018.01044
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发表时间：
2018
影响因子：
5.6
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Gong X;Sun R;Gao Z;Han W;Liu Y;Zhao L;Jing L;Yao X;Sun X
巨胞饮作用是一种高度保守的内吞过程，其特征是细胞外液及其内容物通过称为巨胞饮体的大的异质空泡被吞噬到细胞中。土贝母皂苷-1（Tubeimoside-1，TBM 1）是从中药土贝母（Bolbostemma paniculatum（Maxim.）TBM 1在多种结直肠癌（CRC）细胞系中刺激大量透明相细胞质空泡的快速积累。这些空泡可以被称为大胞饮体，有效地吞噬荧光黄。这些囊泡不与内吞细胞器示踪剂，如ERTracker，LysoTracker和mitoTracker重叠。这些由TBM 1诱导的空泡部分并入溶酶体。透射电子显微镜显示膜皱褶形成板状伪足。突起塌陷到质膜上，然后与质膜融合，产生这些大的内吞空泡。值得注意的是，TBM 1在体内有效地将葡聚糖运输到异位异种移植物中，从而提供了空泡化可以主要被定义为巨胞饮的巩固证据。TBM 1下调细胞活力并增加PI阳性，但不突出Hoechst 33342阳性细胞。TBM 1诱导的细胞死亡可归因于通过过度刺激巨胞饮作用的方法，而巨胞饮作用可被阿米洛利衍生物5-（Nethyl-N-isopropyl）损害。轻链3 II被募集到这些囊泡中以刺激巨胞饮作用。氯喹能明显中和细胞死亡和空泡形成，但3-甲基腺嘌呤不能抑制细胞死亡和空泡形成。TBM 1在体内可协同5-FU发挥减毒增效作用，增加5-FU的摄取而不损伤肝脏。总之，TBM 1有效地诱导体外和体内巨胞饮作用，其可以将小分子运输到CRC细胞中。它是一种有吸引力的药物转运蛋白，可以作为具有翻译潜力的化疗药物。
Macropinocytosis is a highly conserved endocytic process which characterizes the engulfment of extracellular fluid and its contents into cells via large, heterogeneous vacuoles known as macropinosomes. Tubeimoside-1 (TBM1) is a low toxic triterpenoid saponin extracted from a traditional Chinese herb Bolbostemma paniculatum (Maxim.). TBM1 stimulates a quick accumulation of numerous phase-lucent cytoplasmic vacuoles in multiple colorectal cancer (CRC) cell lines. These vacuoles can be termed as macropinosomes that efficiently engulf lucifer yellow. These vesicles are not overlaps with endocytic organelle tracers, such as ERTracker, LysoTracker and mitoTracker. These vacuoles induced by TBM1 partially incorporate into lysosomes. Transmission electron microscope indicates membrane ruffling to form lamellipodia. Protrusions collapse onto and then fuse back with the plasma membrane to generate these large endocytic vacuoles. Notably, TBM1 efficiently trafficks dextrans into heterotopic xenografts in vivo, thus provide consolidated evidence that the vacuolization can be mainly defined as macropinocytosis. TBM1 downregulates cell viability and increases PI-positive, but not highlighted Hoechst 33342-positive cells. TBM1 induced cell death can be ascribed as methuosis by hyperstimulation of macropinocytosis which can be compromised by amiloride derivative 5-(Nethyl-N-isopropyl). Light chain 3 II is recruited to these vesicles to stimulate macropinocytosis. The cell death and vacuoles can be significantly neutralized by chloroquine, but can not be the inhibited by 3-methyladenine. TBM1 can coordinate with 5-FU to exert toxicity reducing and efficacy enhancing effects in vivo by increasing the uptake of the latter without hepatic injury. In conclusion, TBM1 effectively induces in vitro and in vivo macropinocytosis which can traffick small molecules into CRC cells. It is an attractive drug transporter and can be harnessed as a chemotherapeutic synergist with translational potential.
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