Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, Guangdong 510006, P.R. China.
Oncol Rep. 2023 Jun;49(6). doi: 10.3892/or.2023.8552. Epub 2023 Apr 21.
Pyroptosis is a newly identified form of cell death, morphologically characterized by excessive cell swelling. In the present study, paclitaxel (PTX) combined with platinum were used as first‑line chemotherapy, against ovarian cancer cells by inducing multiple types of cell death. However, it remains unclear whether PTX can induce pyroptosis in ovarian cancer cells. It was recently reported that PTX inhibited chloride channels, an inhibition known to cause cell swelling. In the present study, it was first verified that pyroptosis‑like cell death, as well as cleaved‑caspase‑3 and cleaved‑gasdermin E (GSDME) were induced by PTX in A2780 ovarian cancer cells. PTX inhibited the background‑ and hypotonicity‑activated chloride currents, promoted intracellular chloride ion accumulation, those manifestations are similar to those of the classic volume‑regulatory anion channel (VRAC) blocker, 4‑(2‑butyl‑6,7‑dichloro‑2‑cy-clopentyl‑indan‑1‑on5‑yl) oxobutyric acid (DCPIB). Of note, both DCPIB and the downregulation of VRAC constituent protein leucine‑rich repeat‑containing 8a themselves could not induce persisted cell swelling and pyroptosis‑like phenotypes. However, they could enhance the effects of PTX in inducing pyroptosis‑like phenotypes, such as marked cell swelling, cell membrane rupture and excessive activation of caspase‑3 and GSDME N‑terminal fragment, which ultimately caused marked pyroptosis in A2780 cells. These findings revealed a potential mechanism of PTX and offered new insights into the effects of a synergistical combination of PTX and VRACs blockers in ovarian cancer chemotherapy.
细胞焦亡是一种新发现的细胞死亡形式，其形态学特征为细胞过度肿胀。本研究采用紫杉醇（PTX）联合铂类作为一线化疗药物，通过诱导多种类型的细胞死亡来治疗卵巢癌细胞。然而，PTX 是否能诱导卵巢癌细胞发生细胞焦亡尚不清楚。最近有研究报道称，PTX 抑制氯离子通道，这种抑制作用会导致细胞肿胀。本研究首先验证了 PTX 可诱导 A2780 卵巢癌细胞发生类似细胞焦亡的细胞死亡，以及切割的胱天蛋白酶-3 和切割的 GSDME。PTX 抑制了背景和低渗激活的氯离子电流，促进了细胞内氯离子的积累，这些表现类似于经典的容积调节阴离子通道（VRAC）阻断剂 4-（2-丁基-6,7-二氯-2-环戊基-茚-1-酮 5-基）氧代丁酸（DCPIB）。值得注意的是，DCPIB 和 VRAC 组成蛋白富含亮氨酸重复序列 8a 的下调本身并不能诱导持续的细胞肿胀和类似细胞焦亡的表型。然而，它们可以增强 PTX 诱导类似细胞焦亡表型的作用，如明显的细胞肿胀、细胞膜破裂以及 caspase-3 和 GSDME N 末端片段的过度激活，最终导致 A2780 细胞发生明显的细胞焦亡。这些发现揭示了 PTX 的潜在机制，并为紫杉醇与 VRAC 阻断剂联合应用于卵巢癌化疗的协同作用提供了新的见解。
