Category Archives: CHK2

Akt, Anti-cancer, anti-tumor, apoptosis, Apoptotic, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, CHK2, Colon Cancer or Colorectal cancer, ER, ER-positive, G0/G1, G1, HER-2, HER-2/neu, Ovarian cancer, PARP, PI3K, PI3K/Akt

Antrodia camphorata

 

Cancer: Leukemia, colorectal., ER+ ovarian cancer

Action: Anti-cancer

Antrodia Camphorata [(M. Zang & C.H. Su) Sheng H. Wu, Ryvarden & T.T.] is a native Taiwanese mushroom which is used in Asian folk medicine. It is also known as Ganoderma camphoratum (M. Zang & C.H. Su) and Taiwanofungus camphoratus [(M. Zang & C.H. Su) Sheng H. Wu, Z.H. Yu, Y.C. Dai & C.H. Su].

Anti-tumor

Mycotherapy is defined as the study of the use of extracts and compounds obtained from mushrooms as medicines or health-promoting agents. An increasing number of studies in the past few years have revealed mushroom extracts as potent anti-tumor agents. Also, numerous studies have been conducted on bioactive compounds isolated from mushrooms reporting the heteropolysaccharides, β-glucans, α-glucans, proteins, complexes of polysaccharides with proteins, fatty acids, nucleoside antagonists, terpenoids, sesquiterpenes, lanostanoids, sterols and phenolic acids, as promising anti-tumor agents (Popović et al., 2013).

Leukemia

Antrodia camphorata (AC) is a native Taiwanese mushroom, which is used in Asian folk medicine as a chemo-preventive agent. The triterpenoid-rich fraction (FEA) was obtained from the ethanolic extract of AC and characterized by high performance liquid chromatography (HPLC). FEA caused DNA damage in leukemia HL60 cells which was characterized by phosphorylation of H2A.X and Chk2. It also exhibited apoptotic effect which was correlated to the enhancement of PARP cleavage and to the activation of caspase 3.

Taken together, these results provide the first evidence that pure AC component inhibits tumor growth in an in vivo model, thereby backing the traditional anti-cancer use of AC in Asian countries (Du et al., 2012).

Colon Cancer

Antrodia camphorata (AC) grown on germinated brown rice (CBR) was studied in HT-29 human colon cancer cells. CBR 80% ethanol EtOAc fraction showed the strongest inhibitory activity against HT-29 cell proliferation. Induction of G0/G1 cell-cycle arrest on human colon carcinoma cell was observed in CBR EtOAc fraction-treated cells. We found that CBR decreased the level of proteins involved in G0/G1 cell-cycle arrest and apoptosis. CBR EtOAc fraction inhibited the β-catenin signaling pathway, supporting its suppressive activity on the level of cyclin D1 (Park, Lim, & Park, 2013).

A new enynyl-benzenoid, antrocamphin O (1,4,7-dimethoxy-5-methyl-6-(3'-methylbut-3-en-1-ynyl)benzo[d][1,3]dioxide), and the known benzenoids antrocamphin A and 7-dimethoxy-5-methyl-1,3-benzodioxole, were isolated from the fruiting bodies of Antrodia camphorata (Taiwanofungus camphoratus). The benzenoids were tested successfully for cytotoxicity against the HT29, HTC15, DLD-1, and COLO 205 colon cancer cell lines (Chen et al., 2013).

ER+ Ovarian Cancer

MTT and colony formation assays showed that Antrodia camphorata (AC) induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector β-catenin (Yang et al., 2013).

References

Chen PY, Wu JD, Tang KY, et al. (2013). Isolation and synthesis of a bioactive benzenoid derivative from the fruiting bodies of Antrodia camphorata. Molecules, 18(7):7600-8. doi: 10.3390/molecules18077600.


Du YC, Chang FR, Wu TY, et al. (2012). Anti-leukemia component, dehydroeburicoic acid from Antrodia camphorata induces DNA damage and apoptosis in vitro and in vivo models. Phytomedicine. doi:10.1016/j.phymed.2012.03.014


Park DK, Lim YH, Park HJ. (2013). Antrodia camphorata Grown on Germinated Brown Rice Inhibits HT-29 Human Colon Carcinoma Proliferation Through Inducing G0/G1 Phase Arrest and Apoptosis by Targeting the β -Catenin Signaling. J Med Food, 16(8):681-91. doi: 10.1089/jmf.2012.2605.


Popovi ć V, Zivkovi ć J, Davidovi ć S, et al. (2013). Mycotherapy Of Cancer: An Update On Cytotoxic And Anti-tumor Activities Of Mushrooms, Bioactive Principles And Molecular Mechanisms Of Their Action. Curr Top Med Chem.


Yang HL, Lin KY, Juan YC, et al. (2013). The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway. J Ethnopharmacol, 148(1):254-65. doi: 10.1016/j.jep.2013.04.023.

ABCG2, AIF, Anti-cancer, apoptosis, ASTC-a-1, A549, CDC25A, Chapter 7 Isolates and Cancer Research, CHK2, Colon Cancer or Colorectal cancer, cytotoxic, Esophageal cancer, G1, Gastric cancer or Stomach cancer, Glioblastoma, ICAM-1, induces apoptosis, LN-229, Lung cancer, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, Ovarian cancer, ROS, SMAD3

Artesunate, oral (See also Injectables)

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).

References

Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B. (2011). Artesunate Induces Oxidative DNA Damage, Sustained DNA Double-Strand Breaks, and the ATM/ATR Damage Response in Cancer Cells. Mol Cancer Ther, 10(12):2224-33. doi: 10.1158/1535-7163.MCT-11-0534.


Fan, Y, Zhang, YL, Yao, GT, & Li, YK. (2008). Inhibition of Artemisunate on the invasion of human colon cancer line SW620. Lishizzhen Medicine and Materia Medica Research, 19(7), 1740-1741.


Liu, L, Zuo, LF, Guo, JW. (2013). Reversal of Multi-drug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett, 6(5): 1475–1481. doi: 10.3892/ol.2013.1545i


Marchion DC, Xiong Y, Chon HS, et al. (2013). Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer. Am J Obstet Gynecol, S0002-9378(13)00827-2. doi: 10.1016/j.ajog.2013.08.004.


Rutteman GR, Erich SA, Mol JA, et al. (2013). Safety and Efficacy Field Study of Artesunate for Dogs with Non-resectable Tumors. Anti-cancer Res, 33(5):1819-27.


Zhao F, Wang H, Kunda P, et al. (2013). Artesunate exerts specific cytotoxicity in retinoblastoma cells via CD71. Oncol Rep. doi: 10.3892/or.2013.2574.


Zhou C, Pan W, Wang XP, Chen TS. (2012). Artesunate induces apoptosis via a Bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. J Cell Physiol, 227(12):3778-86. doi: 10.1002/jcp.24086.


Zhou X, Sun WJ, Wang WM, et al. (2013). Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. Anti-cancer Drugs, 24(9):920-7. doi: 10.1097/CAD.0b013e328364a109.