Enhancing conventional chemotherapy drug cisplatin-induced anti-tumor effects on human gastric cancer cells both in vitro and in vivo by Thymoquinone targeting PTEN gene

Abstract

Combination chemotherapy regimen with several anti-tumor drugs is a strategy to improve outcome. Thymoquinone (TQ) has been reported to exert biological activity on various types of human cancers without obvious toxicity. However, only few studies showed the anti-tumor effects of TQ combination with cisplatin on gastric cancer (GC). Here, we showed pretreatment with 5μM TQ significantly increased the apoptotic effects induced by cisplatin on GC cell lines. Combined treatment of cisplatin with TQ represented a significantly superior tumor suppression effect than either agent alone in a xenograft tumor mouse model. Interestingly, TQ pretreatment following cisplatin caused a significant increase in the levels of PTEN, an obvious decrease in p-AKT, CyclinD1, P-glycoprotein (P-gp), meanwhile, TQ and cisplatin also led to an increase in Bax, Cyt C, AIF, cleaved caspase 9, and cleaved caspase 3, and a decrease in Bcl-2, procaspase-9, procaspase-3. Moreover, results in vitro, showed that a combination of TQ and cisplatin represents a more effective anti-tumor agent than either agent alone in a xenograft tumor mouse model. In conclusion, TQ significantly augments cisplatin-induced anti-tumor effects on gastric cancer both in vitro and in vivo, through inhibiting PI3K/AKT signaling pathway, activating the mitochondrial pathway, and down-regulating P-glycoprotein by up-regulating PTEN gene. TQ might be as a promising candidate as a cancer chemopreventive or chemotherapeutic agent for antineoplastic combination therapy and merits further clinical investigation.

Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets

“…Cell survival depends on the balance between cell proliferation and apoptosis. TQ has been found to inhibit the survival of many cancer cells derived from breast cancers [ 65 , 67 , 77 , 83 ], pancreatic cancer [ 84 ], gastric cancer [ 85 ], primary effusion lymphoma [ 43 ], prostate cancer [ 86 , 87 ], kidney cancer [ 88 ], squamous cell carcinoma [ 89 ], renal cell carcinoma [ 90 ], and cholangiocarcinoma [ 63 ], primarily through attenuation of the activity of AKT, a crucial kinase associated with cell survival. TQ inhibits the activation of AKT through ROS-dependent mechanisms and/or through activation of the lipid phosphatase, phosphatase and tensin homolog (PTEN).…”

Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways

“… 59 In this context, hypermethylation-mediated epigenetic silencing of the tumor suppressor gene PTEN was observed in activated hepatic stellate cells 60 and stromal fibroblasts. 61 Interestingly, TQ was shown to increase the expression of PTEN gene in gastric cancer both in vitro and in vivo , 62 triple-negative breast cancer 63 and thyroid cancers 64 supporting the idea that TQ could be efficient anti-leukemic drug through targeting the epigenetic code of tumor-associated stromal cells increasing the sensitivity to chemotherapy.…”

PTEN, a Barrier for Proliferation and Metastasis of Gastric Cancer Cells: From Molecular Pathways to Targeting and Regulation

“…In regard to the regulation of PTEN by antitumor agents in GC therapy, the following outcomes may occur: The antitumor compounds are able to affect PTEN in a time- and dose-dependent manners, They can induce PTEN signaling [ 201 , 202 , 203 ], They suppress the PI3K/Akt signaling pathway [ 204 ], They are capable of regulating upstream mediators of PTEN, such as HDAC1 [ 205 ], They inhibit the development of chemoresistance in GC cells [ 206 ], And, finally, they interfere with proliferation and invasion of GC cells via targeting PTEN [ 207 ]. …”