Abstract
AimTo investigate the inhibitory effect of pseudolaric acid B on subcutaneous xenografts of human gastric adenocarcinoma and the underlying molecular mechanisms involved in its multidrug resistance.MethodsHuman gastric adenocarcinoma SGC7901 cells and drug-resistant SGC7901/ADR cells were injected into nude mice to establish a subcutaneous xenograft model. The effects of pseudolaric acid B with or without adriamycin treatment were compared by determining the tumor size and weight. Cyclo-oxygenase-2, protein kinaseC-α and P-glycoprotein expression levels were determined by immunohistochemistry and western blot.ResultsPseudolaric acid B significantly suppressed the tumor growth induced by SGC7901 cells and SGC7901/ADR cells. The combination of pseudolaric acid B and the traditional chemotherapy drug adriamycin exhibited more potent inhibitory effects on the growth of gastric cancer in vivo than treatment with either pseudolaric acid B or adriamycin alone. Protein expression levels of cyclo-oxygenase-2, protein kinaseC-α and P-glycoprotein were inhibited by pseudolaric acid B alone or in combination with adriamycin in SGC7901/ADR cell xenografts.ConclusionPseudolaric acid B has a significant inhibitory effect and an additive inhibitory effect in combination with adriamycin on the growth of gastric cancer in vivo, which reverses the multidrug resistance of gastric neoplasm to chemotherapy drugs by downregulating the Cox-2/PKC-α/P-gp/mdr1 signaling pathway.
Highlights
Gastric cancer is one of the world’s most common cancers [1], and chemotherapy is an important strategy against gastric cancer [2]
It has been discovered that the major reason for multidrug resistance (MDR) in cancer is the overexpression of P-glycoprotein (P-gp), a product of the human MDR1 gene
The aim of the present study is to evaluate the anti-neoplastic effect of PAB in vivo, including the reversal of MDR, using a xenograft model in nude mice and explore whether PAB’s underlying molecular mechanism is related to the inhibition of MDR via the Cox-2/PKC-a/P-gp pathway
Summary
Gastric cancer is one of the world’s most common cancers [1], and chemotherapy is an important strategy against gastric cancer [2]. Because multiple chemotherapeutic drugs of different classes are used to treat gastric cancer, the sensitivity of anticancer drugs to gastric cancer decreases gradually, and resistance to many different drugs with different chemical structures and different mechanisms of action can occur. This type of resistance is called multidrug resistance (MDR) and significantly decreases the efficiency of therapy on gastric cancer. MDR is becoming a major problem for successful cancer treatment [3]. It has been discovered that the major reason for MDR in cancer is the overexpression of P-glycoprotein (P-gp), a product of the human MDR1 gene. Recent studies have demonstrated that in cancer cells with MDR, the expression levels of cyclo-oxygenase-2 (Cox-2) and an isoform of protein kinaseC (PKC-a) are both upregulated, and their inhibition can reverse neoplastic MDR [5,6,7,8,9,10]
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