Anti-cancer activity of DHA on gastric cancer—an in vitro and in vivo study

Abstract

Treatment of gastric cancer remains a major challenge, and new anticancer drugs are urgently required. This study investigated whether dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, could inhibit the growth of gastric cancer both in vitro and in vivo. A series of in vitro experiments including MTT, colony-forming, wound healing, invasion, cell cycle, cellular senescence, and apoptosis assays were performed to examine the antiproliferative and antimetastatic effects of DHA on three gastric cancer cell lines, SGC-7901, BGC823, and MGC803. The result showed that the proliferation rate and colony-forming abilities of gastric cancer cells were significantly suppressed by DHA together with significant suppression of the expressions of proliferation markers (PCNA, cyclin E, and cyclin D1), and upregulation of p21 and p27. Moreover, DHA induced cellular senescence, G1 phase cell cycle arrest and hindered the migration and invasion of gastric cancer cells corresponding with downregulation of MMP-9 and MMP-2. Furthermore, DHA significantly induced apoptosis through suppressing Bcl-2 as well as activating caspase-9 and PARP. Treatment of gastric cancer cells with DHA increased miR-15b and miR-16 expression, caused a downregulation of Bcl-2, resulting in apoptosis of gastric cancer cells. In vivo, our data showed that DHA significantly inhibited the growth of SGC7901 cell-transplanted tumors. In summary, we have shown that DHA is able to inhibit the growth and metastasis of human gastric cancer. The modulation of miR-15b and miR-16 mediated the apoptosis effects of DHA in gastric cancer cells. Our work suggested that DHA has significant anticancer effects against gastric cancer both in vivo and in vitro, indicating that it is a promising therapy for human gastric cancer.

Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

“…5e), corroborating the dominant role of Bak in DHA-induced intrinsic apoptosis in HCC cells [27]. In contrast, the Bax-mediated intrinsic pathway has been reported to play a key role in DHAinduced apoptosis in various cell lines [13,[18][19][20][21][22][23][24]. Therefore, the pro-apoptotic action of DHA is cell typedependent.…”

“…Although reactive oxygen species (ROS) generated from the endoperoxide bridge contained in DHA contributes to the potent cytotoxic effects of DHA on cancer cells, DHA triggers different apoptotic pathways to mediate cell apoptosis [17]. Accumulated proofs have shown the important role of the Bax-dependent intrinsic apoptosis pathway in DHA-induced apoptosis of multiple types of cancer cells [15,[18][19][20][21][22]. Our recent studies also demonstrated that the Bax-mediated intrinsic apoptosis pathway played a dominant role in DHA-induced apoptosis of lung cancer cells [20,23,24], while the Bak-mediated intrinsic apoptosis pathway controlled the pro-apoptotic actions of the combined treatment with DHA and gemcitabine in inducing apoptosis of A549 cells [13].…”

Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis

“…Apoptosis induced by DHA in different cancer cells has been reported [21][22][23][24][25][26][27][28][29][30]. In the present study, we examined apoptosis in human androgen-independent PC3 prostate cancer cells after DHA treatment, by flow cytometry and TEM.…”

“…Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin isolated from the Chinese medicinal plant Artemisia annua L., has been widely used as an effective antimalarial drug [15][16][17][18][19]. Recently, many studies have shown that DHA is the most potent anticancer agent among artemisinin and its derivatives [20], and has in vitro and in vivo anticancer activity in different types of human cancer cells, such as hepatocellular carcinoma, prostate cancer, gastric cancer, osteosarcoma, breast cancer, esophageal cancer, pancreatic cancer, lung cancer, and ovarian cancer [21][22][23][24][25][26][27][28][29][30][31]. It has been demonstrated that DHA can induce apoptosis and/or inhibit proliferation of cancer cells [21][22][23][24][25][26][27][28][29][30][31].…”

Mangiferin regulates proliferation and apoptosis in glioma cells by induction of microRNA-15b and inhibition of MMP-9 expression

“…Zheng et al (24) reported that miR-15b deactivated the MEK-ERK pathway through MMP-3 in 9L glioma cells. Sun et al (25) suggested that treatment of gastric cancer cells increased miR-15b expression corresponding with downregulation of MMP-9 and MMP-2.…”