Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells

Lu, Jin‐Jian; Meng, Ling; Shankavaram, Uma; Zhu, Changtai; Tong, Lihong; Chen, Guang; Lin, Liang‐Hung; Weinstein, John N.; Ding, Jian

doi:10.1016/j.bcp.2010.02.016

Cited by 70 publications

(75 citation statements)

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“…2). Consistent with our results, previous studies showed that DHA alone exhibits antitumor activity in lung, breast, colon, and pancreatic cancer by suppressing proliferation (20). We also observed that Jurkat cells were sensitive to siNotch1 alone in vitro (Fig.…”

Section: Discussionsupporting

confidence: 92%

Effect of dihydroarteminin combined with siRNA targeting Notch1 on Notch1/c-Myc signaling in T-cell lymphoma cells

Huo

Wei

et al. 2018

Exp Ther Med

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Section: Discussionsupporting

confidence: 92%

Effect of dihydroarteminin combined with siRNA targeting Notch1 on Notch1/c-Myc signaling in T-cell lymphoma cells

Huo

Wei

et al. 2018

Exp Ther Med

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“…The antimalaria drugs artesunate (ART) and dihydroartemisinin (DHA) have been reported to downregulate c-MYC. 15 In addition, in MM cells, treatment with ART or DHA led to induction of apoptosis concomitant with downregulation of c-MYC protein ( Figure 2B-C). In contrast, lethal doses of PS-341 (bortezomib) did not decrease c-MYC expression ( Figure 2B-C).…”

Section: Resultsmentioning

confidence: 88%

Addiction to c-MYC in multiple myeloma

Holien

Våtsveen

Hella

et al. 2012

Blood

156

138

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IntroductionMembers of the MYC family are important oncogenes involved in the development of malignant cells. 1 This may also be the case in multiple myeloma (MM), a malignancy of antibodyproducing plasma cells in bone marrow. The activity of c-MYC in MM increases with disease stage. 2,3 The mechanism by which c-MYC is activated in each case is unclear; however, multiple signaling pathways converge on c-MYC. Translocations involving MYC and immunoglobulin genes (IG) are relatively rare in MM and considered late progression events. 4 c-MYC regulates transcription of up to 15% of the genes in human cells by binding to its obligate partner MAX. Many cancer cells may develop a dependency on c-MYC activity; and by preventing this activity, the cells may stop dividing or even undergo apoptosis. In agreement with this, short-hairpin RNA targeting MYC was shown to be lethal to a number of human myeloma cell lines. 5 A small-molecule inhibitor, termed 10058-F4, has been identified that is proposed to specifically inhibit c-MYC-MAX heterodimerization, thereby preventing transactivation of c-MYC target genes. 6,7 The inhibitor has been shown to have growth inhibitory effects on lymphoma and acute myelogenous leukemia cells. 8,9 Methods CellsMyeloma cell lines used in this study were U266, INA-6, JJN-3, KMS-12-BM, IH-1, and KJON. Details on cell culture conditions are found in supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). CD138 ϩ patient cells obtained through the Norwegian Myeloma Biobank were purified using RoboSep automated cell separator and Human CD138 Positive Selection Kit (Stem Cell Technologies). Bone marrow stromal cells (BMSCs) from patients were obtained by plastic adherence and cultivated as stated in supplemental Methods. The project was approved by the Regional Ethics Committee, and patients gave informed consent in accordance with the Declaration of Helsinki. Patient characteristics are described in supplemental Table 1.Cell viability measurements and quantitative RT-PCR were performed as described previously. 10 PCR TaqMan assays used were as follows: MYC, Hs00153408_m1; MYCL1, Hs00420495_m1; and GAPDH, Hs99999905_m1 (Applied Biosystems).Description of other reagents, immunoblotting, and knockdown experiments is found in supplemental Methods. Results and discussionTo address the c-MYC dependency of myeloma cells, we decided to evaluate the effect of 10058-F4 in myeloma cell lines and primary cells by in vitro studies. First, both mRNA and protein expression of c-MYC and L-MYC was determined in 6 cell lines by quantitative RT-PCR and immunoblotting ( Figure 1A). Five of the cell lines expressed c-MYC, whereas U266 only had L-MYC, as previously reported. 11 L-MYC mRNA was also detected in KMS-12-BM and to a lesser extent in INA-6 and JJN-3, although the levels of L-MYC were negligible compared with c-MYC. The effect on cell viability was evaluated in myeloma cell lines treated with increasing concentrations of 10058-F4 for 48 hour...

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“…In addition, the type of derivative was proved to target G 1 phase of the cell cycle [41] . Thus far, antitumor activity of artemisinins and the underlying mechanisms have been www.nature.com/aps Li Y Acta Pharmacologica Sinica npg widely studied [43][44][45][46][47][48][49] , however, few clinical trials were reported. Antimalarial chloroquine was used as immunosuppressive agent.…”

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confidence: 99%

Qinghaosu (artemisinin): Chemistry and pharmacology

2012

Acta Pharmacol Sin

124

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Qinghaosu and its derivatives are widely used in the world as a new generation of antimalarial drug. Up to now, some important progresses of Qinghaosu research have been made, including synthesis of new Qinghaosu derivatives and analogs, investigation on their bioactivities and mode of actions. The present review briefly describes these efforts made by researchers in China, particularly in this Institute.Keywords: Qinghaosu; artemisinin; structure modification; antimalarial activity; anticancer activity; immunosuppressive activity; mode of action Acta Pharmacologica Sinica (2012) 33: 1141-1146; doi: 10.1038/aps.2012.104; published online 27 Aug 2012On 23rd May 1967, China established National Steering Group on antimalarial drug research, more than 60 institutes and 500 researchers joined in this project. After screening of over 5000 traditional Chinese medicines, Qinghaosu (QHS), an antimalarial principle, was isolated from Artemisia annua L in 1972 [1,2] . At the end of 1975, its unique chemical structure was elucidated, as a sesquiterpene lactone bearing a peroxy group, quite different from that of all known antimalarial drugs [3] .Early pharmacological and clinic studies showed QHS have rapid onset of action, low toxicity and high effect on both drug-resistant and drug-sensitive malaria. However, its shortcomings (poor solubility in water or oil; high rate of parasite recrudescence) needed to be overcome. In 1976, our Institute was charged with this important mission, and a research in relationship between chemical structure and activity immediately started.First of all, the function of peroxy group for antimalarial activity was examined. The negative result of deoxyqinghaosu (Scheme 1) against P berghei in mice demonstrated that the peroxy group was essential. Soon afterwards, it was found that some other simple peroxides including monoterpene ascaridol had no antimalarial activity. These experimental results proved peroxy group to be an essential but not a sufficient factor. At that time, we noted the molecule contained a rare segment -O-C-O-C-O-C=O, and realized that whole molecular skeleton might play an important role for antimalarial activity.When dihydroartemisinin (DHA) was found to be more active than QHS, but was still with poor solubility and lower stability (as a lactol) than QHS, we decided to prepare its derivatives. In 1976-1977, over 50 derivatives of DHA were synthesized (Scheme 1) and evaluated [4,5] .The first 25 compounds (in oil solution) were tested in mice infected chloroquine-resistant P berghei though intramuscular injection [6] . Most of these derivatives showed higher activity than QHS (SD 50 6.20 mg/kg) and DHA (SD 50 3.65 mg/kg). In the ether series, SM 224 (R=CH 3 , SD 50 1.02 mg/kg) is more

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Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells

Cited by 70 publications

References 47 publications

Effect of dihydroarteminin combined with siRNA targeting Notch1 on Notch1/c-Myc signaling in T-cell lymphoma cells

Effect of dihydroarteminin combined with siRNA targeting Notch1 on Notch1/c-Myc signaling in T-cell lymphoma cells

Addiction to c-MYC in multiple myeloma

Qinghaosu (artemisinin): Chemistry and pharmacology

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