Halofuginone inhibits colorectal cancer growth through suppression of Akt/mTORC1 signaling and glucose metabolism

Chen, Guoqing; Tang, Chengfang; Shi, Xiaoke; Lin, Chengyuan; Fatima, Sarwat; Pan, Xiaohua; Yang, Da; Zhang, Ge; Lu, Aiping; Lin, Shuhai; Bian, Zhaoxiang

doi:10.18632/oncotarget.4376

Cited by 54 publications

(51 citation statements)

References 45 publications

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“…For example, ATS has anti-proliferation effects on human breast cancer [7], neuroblastoma [8] and ishikawa endometrial cancer [9]. HF also has the ability to inhibit the proliferation of human colorectal cancer cells [10], multiple myeloma cells [11], and liver cancer cells [12]. According to the history of using the formula of Qinghao and Changshan in TCM, we hypothesize that HF and ATS could exhibit synergistic anticancer effect.…”

Section: Introductionmentioning

confidence: 99%

Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1

et al. 2016

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Combinational drug therapy is one of the most promising strategies in modern anticancer research. Traditional Chinese medicine (TCM) formulas represent a wealth of complex combinations proven successful over centuries of clinical application. One such formula used to treat a variety of diseases, including cancer, contains two herbs, whose main active components are Halofuginone (HF) and Artemisinin (ATS). Here we studied the anticancer synergism of HF and ATS in various cancer cell lines and in a xenograft nude mice model. We found that the HF-ATS combination arrested more cells at the G1/G0 phase than either one alone, with the concomitant increased levels of CDK2 inhibitors, p21Cip1 and p27Kip1. By knocking down p21Cip1 and p27Kip1 separately or simultaneously in HCT116 cells and MCF-7 cells, we found that p21Cip1 was required for HF induced G1/G0 arrest, whereas p21Cip1 and p27Kip1 were both required for ATS or HF-ATS combination-mediated cell cycle arrest. Moreover, HF-ATS combination synergistically inhibited tumor growth in xenograft nude mice, and this was associated with the increased levels of p21Cip1 and p27Kip1. Collectively, these data indicate that the upregulation of p21Cip1 and p27Kip1 contributes to the synergistic anticancer effect of the HF-ATS combination.

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Section: Introductionmentioning

confidence: 99%

Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1

et al. 2016

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“…In the literature, the effect of HLF on colon cancer has been examined in the nude mouse (Chen et al, 2015), but its effects on TNF-, IL-2, IL-6 and IL-10 levels, ACF score, the main marker of colon cancer, PGM and TBARS levels have not been investigated.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that HLF may induce apoptosis and reduce cancer volume in experimentally induced colon cancer in the nude mouse (Chen et al, 2015). It may also have antiangiogenic, antimetastatic and antiproliferative effects, increase apoptosis/necrosis, and decrease collagen content in other cancer types (Gavish et al, 2002;Grudzien et al, 2010;Jordan and Zeplin, 2012).…”

Section: Resultsmentioning

confidence: 99%

Halofuginone may suppresses azoxymethane-induced serum tumor necrosis factor-a synthesis and aberrant crypt foci progression in rat colon

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Yazar

2017

IJAR

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The aim of this research was to investigate the effect of halofuginone on the progression of azoxymethane-induced colon cancer in rats. A total of 38 male Wistar albino rats were divided into 4 groups: Control (n=8), Halofuginone (n=10, 0.4 mg/ kg, PO, SID), Cancer (n=10, azoxymethane, 15 mg/kg, IP, once a week for two weeks) and Cancer + Halofuginone (n=10). After 18 weeks, blood samples were taken under anesthesia and all animals were sacrificed. Aberrant crypt foci in the colon were stained with methylene blue. Blood cytokines, thiobarbituric acid reactive substances, 13,14-dihydro-15-ketoprostaglandin F2 levels, hemogram and biochemical values were measured. The tumor necrosis factor-a level in the Cancer group was higher (P<0.05) than in other groups, while higher numbers of aberrant crypt foci were found in the Cancer group compared with the Cancer + Halofuginone group (P<0.05). In summary, it may be stated that halofuginone may warrant evaluation as a supportive drug in the treatment of colon cancer in the future.

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“…A recent study demonstrated that halofuginone (HF) had a potent anticancer activity and slowed glycolysis via suppressing Akt/mTORC1 signaling and glucose metabolism. In HF-treated human colorectal cancer cells, there was a reduction in mTORC1 and phosphorylation of Akt, causing a rapid decrease in HK2 and Glut1 [66] . We recently found a novel role for eEF-2K, a negative regulator of protein synthesis, in promoting glycolysis and in tumor development and progression and the underlying molecular mechanism.…”

Section: Anti-cancer Therapy Based On the Warburg Effectmentioning

confidence: 99%

Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

et al. 2016

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Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity.

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Halofuginone inhibits colorectal cancer growth through suppression of Akt/mTORC1 signaling and glucose metabolism

Cited by 54 publications

References 45 publications

Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1

Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1

Halofuginone may suppresses azoxymethane-induced serum tumor necrosis factor-a synthesis and aberrant crypt foci progression in rat colon

Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

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