Kanglaite inhibits the expression of drug resistance genes through suppressing PVT1 in cisplatin-resistant gastric cancer cells

Abstract

Abstract. Kanglaite (KLT) was shown to alleviate the development of multidrug resistance (MDR) clinically. The purpose of this study is to examine the mechanism of KLT for chemotherapy resistance in gastric cancer cells involving the regulation of MDR-related proteins. The cisplatin-resistant BGC823/DPP and SGC7901/DDP cells were treated with 1, 2.5 and 5 µl/ml of KLT for 24, 36 and 48 h. Cell Counting Kit-8 (CCK-8) assay and flow cytometry were performed to detect the cell viability and cell apoptosis, respectively. The expression of MDR1 and multidrug resistance associated protein 1 (MRP1) were examined by quantitative PCR and western blotting in BGC823/DPP cells and SGC7901/DDP cells treated with KLT. The effect of KLT on the expression of PVT1 was investigated. PVT1-overexpression vector was constructed and transfected into BGC823/DPP cells and SGC7901/DDP cells which were treated with KLT. KLT inhibited the cell viability and promoted the cell apoptosis of BGC823/DPP cells and SGC7901/DDP cells in a concentration-dependent manner. KLT suppressed the expression of MDR1 and MRP1 and the level of PVT1. PVT1 overexpression reversed the increased percentage of apoptotic cells induced by KLT. Finally, we found that PVT1 overexpression also abrogated the effect of KLT on the mRNA level and protein level of MDR1 and MRP1 in BGC823/DPP and SGC7901/DDP cells. KLT inhibited the expression of MDR1 and MRP1 via suppressing the expression of PVT1, which suggested the potential mechanism of KLT involving in MDR in gastric cancer.

<p>A Review of Research Progress in Multidrug-Resistance Mechanisms in Gastric Cancer</p>

“…131,132 And in the prescription of drug resistance in gastric cancer, up-regulating PVT1's expression would raise the expression of p-glycoprotein, MRP, mTOR and HIF-1α to induce multidrugresistance, while inhibiting PVT1's expression would reverse cell resistance to cisplatin. 133,134 Other studies have shown that down-regulating the expression of LEIGC in gastric cancer cells could enhance the resistance to 5-fluorouracil via regulating the EMT process, which suggested LEIGC could be a suppressor lncRNA in gastric cancer. 135 Further studies have found that the target site of lncRNA MRUL is close to p-glycoprotein, and the expression of MRUL is higher in drug-resistance cells.…”

Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma

“…Thus, enhanced MRP1 expression in GAC cells obtained from naïve patients after cisplatin treatment and in the cisplatin-resistant GAC cell line KATOIII/DDP has been found [22]. Indirect evidence further supports that MRP1 is involved in cisplatin resistance [23,24]. MRP1 overexpression in vitro reduced the cytotoxic effect of doxorubicin, whereas tanshinone IIA (an abietane diterpene) potentiated doxorubicin effect, even in resistant GAC cells, by MRP1 inhibition [25].…”

Efficacy and safety of Kanglaite injection for gastric cancer

“…It is also the first Chinese medicine approved by the US Food and Drug Administration, and has been used as a biphasic broad-spectrum antitumor drug in clinical trials in the United States. [ 16 , 17 ] Millions cancer patients in more than 2000 hospitals in China have been treated with Kanglaite injection. [ 18 ] It has been widely used for the treatment of Pancreatic cancer, [ 19 , 20 ] lung cancer, [ 21 , 22 ] breast cancer, [ 23 ] colorectal cancer, [ 24 ] hepatocellular carcinoma, [ 25 ] and GC.…”

“…[ 26 , 27 ] Researches showed that Kanglaite injection could effectively reverse multiple-drug resistance in cancer cells and enhance the sensitivity of tumor cells to chemotherapeutic drugs. [ 17 , 27 – 29 ]…”