A novel imidazopyridine analogue as a phosphatidylinositol 3-kinase inhibitor against human breast cancer

Lee, Hyunseung; Li, Guangyong; Jeong, Yujeong; Jung, Kyung Hee; Ham, Kyungrok; Hong, Sungwoo; Hong, Soon‐Sun

doi:10.1016/j.canlet.2011.12.001

Cited by 16 publications

(11 citation statements)

References 27 publications

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“…Clinical studies indicate that the combination of gemcitabine and various anticancer drugs is needed for survival prolongation, although previous uses of combination therapies have Pancreatic cancers are associated with high incidence of K-ras mutations with increased signaling through the PI3K/Akt pathway and the cancer cells show high Akt activation (16), suggesting PI3K/Akt as a target for gemcitabine combinations. In addition, we previously reported that HS-104, a novel PI3K inhibitor, inhibited tumor growth by inhibiting PI3K/Akt signaling in hepatocellular carcinoma and breast cancer (22,23). These findings have led us to investigate the combination effect of gemcitabine and HS-104 in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 97%

“…HS-104 is a synthetic PI3K inhibitor belonging to the imidazopyridine derivative class (21). In our previous study, we reported that HS-104 suppressed tumor proliferation and angiogenesis in various cancers (22,23). On the basis of our previous findings, we decided to combine gemcitabine and HS-104, which may represent a major advantage over traditional chemotherapies.…”

Section: Hs-104 a Pi3k Inhibitor Enhances The Anticancer Efficacy Omentioning

confidence: 99%

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HS-104, a PI3K inhibitor, enhances the anticancer efficacy of gemcitabine in pancreatic cancer

Jung

Zhang

Fang

et al. 2014

International Journal of Oncology

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Gemcitabine has limited clinical benefits for pancreatic cancer patients. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is important in cell proliferation and survival, and is frequently dysregulated in pancreatic cancer. To obtain insights into novel therapeutic strategies for treating pancreatic cancer, we investigated whether HS-104, a novel PI3K inhibitor, in combination with gemcitabine would show a synergistic effect in pancreatic cancer. We first evaluated the effect of gemcitabine alone or in combination with HS-104 on cell viability. When administered together, the two drugs synergistically inhibited the viability of AsPC-1 and PANC-1 cells, and decreased mitochondrial membrane potential, thereby inducing apoptosis. Compared to the treatment with either drug alone, the combination treatment resulted in apoptosis accompanied by increased levels of cleaved caspase-3 and Bax. These results were consistent with decreased expression of p-Akt, p-mTOR, p-Mek and p-Erk. Moreover, the combination treatment inhibited blood vessel formation in a Matrigel plug assay in mice. Furthermore, in vivo, the combination significantly inhibited tumor growth and enhanced apoptosis by increasing the number of TUNEL-positive cells, and cleaved caspase-3 together with decreasing the expression of angiogenesis- and proliferation-related effectors such as CD34 and PCNA in tumor tissues, compared with each drug alone. Taken together, our study demonstrates that the combination of gemcitabine and HS-104 had a synergistic anticancer effect and inhibited the PI3K/Akt and RAF/Mek pathways on pancreatic cancers. On the basis of our results, we suggest that the combination of these two drugs may be considered as a new therapeutic regimen for treating pancreatic cancer.

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Section: Discussionmentioning

confidence: 97%

Section: Hs-104 a Pi3k Inhibitor Enhances The Anticancer Efficacy Omentioning

confidence: 99%

HS-104, a PI3K inhibitor, enhances the anticancer efficacy of gemcitabine in pancreatic cancer

Jung

Zhang

Fang

et al. 2014

International Journal of Oncology

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“…Other in vitro studies similarly demonstrated LNCaP cells grown in SR medium for extended periods of time have increased Akt activation which may compensate for a lack of androgen signaling [ 12 ]. Indeed, there is high prevalence of PI3K/Akt/mTOR pathway activation in CR PCa and emerging studies show inhibitors targeting the PI3K/Akt pathway are rapidly entering into clinical trials [ 14 , 53 – 55 ]. Therefore, the PI3K/Akt signaling axis is a promising next-in-line therapeutic target and its inhibition in conjunction with ADT and anti-androgens may improve patient survival.…”

Section: Discussionmentioning

confidence: 99%

Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

et al. 2015

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Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

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“…Although HS-133 is very similar to the pharmacological mechanism of IPD-196, a previously reported PI3K inhibitor, the potency is distinctly different [ 41 ]. In addition, the IC 50 of HS-133 was higher than the other PI3K inhibitor without fluorescence such as HS-104 in breast cancer [ 42 ]. Thus, we need to further develop the potent PI3K inhibitors with fluorescent function.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we observed that HS-133 is more efficient than other previously reported PI3K inhibitors in human breast cancer. For example, although the IC 50 of HS-104 (4.8 μM) was more effective by approximately 8 folds than HS-133 (32 μM) in SkBr3 cells, tumor growth inhibition was shown at the lower dose of HS-133 compared to HS-104 against SkBr3-bearing xenograft mice (respectively 10 mg/kg/d, 20 mg/kg/d) [ 42 ]. The reason why HS-133 showed better effect in our experiments may be due to good oral bioavailability.…”

Section: Discussionmentioning

confidence: 99%

HS-133, a novel fluorescent phosphatidylinositol 3-kinase inhibitor as a potential imaging and anticancer agent for targeted therapy

et al. 2014

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As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer.

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A novel imidazopyridine analogue as a phosphatidylinositol 3-kinase inhibitor against human breast cancer

Cited by 16 publications

References 27 publications

HS-104, a PI3K inhibitor, enhances the anticancer efficacy of gemcitabine in pancreatic cancer

HS-104, a PI3K inhibitor, enhances the anticancer efficacy of gemcitabine in pancreatic cancer

Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

HS-133, a novel fluorescent phosphatidylinositol 3-kinase inhibitor as a potential imaging and anticancer agent for targeted therapy

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