Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death. Chemotherapy resistance remains the major reason for GC treatment failure and poor overall survival of patients. Our previous studies have proved that Zuo Jin Wan (ZJW), a traditional Chinese medicine (TCM) formula, could significantly enhance the sensitivity of cisplatin (DDP)-resistant gastric cancer cells to DDP by inducing apoptosis via mitochondrial translocation of cofilin-1. However, the underlying mechanism remains poorly understood. This study aimed to evaluate the effects of ROCK/PTEN/PI3K on ZJW-induced apoptosis in vitro and in vivo. We found that ZJW could significantly activate the ROCK/PTEN pathway, inhibit PI3K/Akt, and promote the apoptosis of SGC-7901/DDP cells. Inhibition of ROCK obviously attenuated ZJW-induced apoptosis as well as cofilin-1 mitochondrial translocation, while inhibition of PI3K had the opposite effects. In vivo, combination treatment of DDP and ZJW (2000 mg/kg) significantly reduced tumor growth compared with DDP alone. Moreover, the combined administration of ZJW and DDP increased the expression of cleaved ROCK and p-PTEN while it decreased p-PI3K and p-cofilin-1, which was consistent with our in vitro results. These findings indicated that ZJW could effectively inhibit DDP resistance in GC by regulating ROCK/PTEN/PI3K signaling and provide a promising treatment strategy for gastric cancer.
Highlights
Gastric cancer (GC) is one of the most prevalent cancers characterized by high morbidity and mortality [1]
To determine whether phosphatase and tensin homolog (PTEN) is a downstream effector of Rho-associated kinase (ROCK) in Zuo Jin Wan (ZJW)-regulated cell apoptosis, we detected the expression of PTEN and pPTEN
The expression level of p-PTEN was upregulated in relation to control in a time dependent manner; the phosphorylation levels of PI3K and Akt were decreased in SGC-7901/DDP cells after ZJW 24 or 48 h treatment (Figure 1(a))
Summary
GC is one of the most prevalent cancers characterized by high morbidity and mortality [1]. Surgery remains the only curative therapeutic methods so far. Due to its late disease presentation, GC was detected in most of the patients at an advanced stage when the tumor is usually migrated, causing an extremely low 5-year survival rate [2]. DDP is considered as a common drug for the treatment of GC [3]. DDP based adjuvant chemotherapy has been approved to increase survival after gastric resection [4]. Intrinsic or acquired drug resistance seriously limits the treatment effect of DDP [4]. It is necessary to develop effective strategies to increase the sensitivity of DDP in GC treatment
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