Cancer:
Non-resectable tumors, Retinoblastoma, colon, esophageal., retinoblastoma, ovarian, lung, glioblastoma, MDR, gastric
Action: Anti-cancer
Artesunate is a semisynthetic derivative of the herbal anti-malaria drug artemisinin, which is the active agent from Artemisia annua L. used in traditional Chinese medicine.
Anti-cancer; Canine
The anti-malarial drug artesunate has shown anti-cancer activity in vitro and in preliminary animal experiments, but experience in patients with cancer is very limited. Preclinical studies in dogs indicated morbidity at high dosage levels. The effects of artesunate have been examined in canine cancer cell lines and in canine cancer patients. A safety/efficacy field study with artesunate was conducted in 23 dogs with non-resectable tumors.
Artesunate was administered for 7–385 days at a dosage of 651-1178 (median 922) mg/m(2). No neurological or cardiac toxicity was observed and seven dogs exhibited no adverse effects at all. Fever and haematological/gastrointestinal toxicity, mostly transient, occurred in 16 dogs. Plasma artesunate and DHA levels fell below the limit of detection within 8–12 hours after artesunate administration, while levels after two hours were close to 1 µM. Artesunate produced a long-lasting complete remission in one case of cancer and short-term stabilization of another 7 cases. This study suggests artesunate may be an effective anti-cancer agent in humans (Rutteman, 2013).
Lung Cancer
The exact molecular mechanism by which artesunate induces apoptosis in human lung adenocarcinoma (ASTC-a-1 and A549) cell lines has been examined, and it was found that artesunate induces apoptosis via a Bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. Artesunate treatment was found to induce ROS-mediated apoptosis in a concentration- and time-dependent fashion accompanying the loss of mitochondrial potential and subsequent release of Smac and AIF indicative of intrinsic apoptosis pathway. Furthermore, although ART treatment did not induce a significant down-regulation of voltage-dependent anion channel 2 (VDAC2) expression and up-regulation of Bim expression, silencing VDAC2 potently enhanced the artesunate-induced Bak activation and apoptosis which were significantly prevented by silencing Bim.
Collectively, our data firstly demonstrate that artesunate induces Bak-mediated caspase-independent intrinsic apoptosis in which Bim and VDAC2 as well as AIF play important roles in both ASTC-a-1 and A549 cell lines, indicating a potential therapeutic effect of artesunate for lung cancer (Zhou, 2012).
Glioblastoma
Trials that include artesunate in cancer therapy are ongoing due to its action as a powerful inducer of oxidative DNA damage, giving rise to formamidopyrimidine DNA glycosylase-sensitive sites and the formation of 8-oxoguanine and 1,N6-ethenoadenine. Oxidative DNA damage was induced in LN-229 human glioblastoma cells dose-dependently and was paralleled by cell death executed by apoptosis and necrosis, which could be attenuated by radical scavengers such as N-acetyl cysteine.
These data indicate that both homologous recombination and nonhomologous end joining are involved in the repair of artesunate-induced DNA double-strand break (DSB). Artesunate provoked a DNA damage response (DDR) with phosphorylation of ATM, ATR, Chk1, and Chk2.
Overall, these data revealed that artesunate induces oxidative DNA lesions and DSB that continuously increase during the treatment period and accumulate until they trigger discoidin domain receptors (DDR) and finally tumor cell death (Berdelle, 2011).
Esophageal Cancer, MDR
The Eca109/ABCG2 cell line was established by transfecting the ABCG2 gene into Eca109 cells. The Eca109/ABCG2 esophageal cancer cells with ABCG2 gene overexpression were resistant to adriamycin (ADM), daunorubicin (DNR) and mitoxantrone (MIT), which indicated that ABCG2 may be associated with drug resistance in esophageal cancer.
Artesunate (ART) exerted profound anti-cancer activity. The mechanism for the reversal of multi-drug resistance by Art in esophageal carcinoma was analyzed using cellular experiments (Liu, Zuo, & Guo, 2013).
Artesunate was found to stop the growth of esophageal cancer cells transplated subcutaneous tumors in nude mice in the G1 stage. It is hence thought that the role of Artesunate against esophageal carcinoma maybe relate to cell-cycle blockage. Artesunate was also found to increase the expression of SMAD3 and TGF-β1, and reduce the expression of CDC25A and CDC25B which may also play a role in its anti-cancer activity.
Retinoblastoma
Zhao et al. (2013) found that the cytotoxic action of artesunate (ART) is specific for Retinoblastoma (RB) cells in a dose-dependent manner, with low toxicity in normal retina cells. ART is more effective in RB than carboplatin with a markedly strong cytotoxic effect on carboplatin-resistant RB cells. RB had higher CD71 levels at the membrane compared to normal retinal cells. ART is a promising drug exhibiting high selective cytotoxicity even against multi-drug-resistant RB cells.
Gastric Cancer
Artesunate has concentration-dependent inhibitory activities against gastric cancer in vitro and in vivo by promoting cell oncosis through an impact of calcium, vascular endothelial growth factor, and calpain-2 expression (Zhou et al., 2013).
Ovarian Cancer
Advanced-stage ovarian cancer (OVCA) has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease. Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration (Marchion et al., 2013).
Colon Cancer
After colon cancer SW620 cells were treated with different doses of Artemisunate, anchorage independence was studied in soft agar colony formation. Invasiveness was assessed by Boyden chamber, and the protein level of intercellular adhesion molecule-1 (ICAM-1) was detected by Western blot assay. Artemisunate significantly inhibited both the invasiveness and anchorage independence in a dose-dependent manner. The protein level of ICAM-1 was down-regulated as relative to the control group.
Artemisunate could potentially inhibit invasion of the colon carcinoma cell line SW620 by down-regulating ICAM-1 expression (Fan, Zhang, Yao, & Li, 2008).
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