Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy

Han, Bingshe; Park, Dongkyoo; Li, Rui; Xie, Mengying; Owonikoko, Taofeek K.; Zhang, Guojing; Sica, Gabriel L.; Ding, Chunyong; Zhou, Jia; Magis, Andrew T.; Chen, Zhuo G.; Shin, Dong M.; Ramalingam, Suresh S.; Khuri, Fadlo R.; Curran, Walter J.; Deng, Xingming

doi:10.1016/j.ccell.2015.04.010

Cited by 110 publications

(126 citation statements)

References 59 publications

(87 reference statements)

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“…A National Cancer Institute (NCI) database library of 300,000 small molecules was docked into the Mcl-1 BH1 structure pocket (aa 256-265) identified by the UCSF DOCK 6.1 program suite for a first round of screening as we previously described (ref. 48 and Figure 8A). The small molecules were ranked according to their energy scores.…”

Section: Discussionmentioning

confidence: 90%

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Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

Guo¹,

Magis²,

Xu³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 90%

“…Lung cancer xenografts were generated as previously described (48). Six-week-old male nude mice were purchased from Harlan and housed under pathogen-free conditions.…”

mentioning

confidence: 99%

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

Guo¹,

Magis²,

Xu³

et al. 2017

Journal of Clinical Investigation

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“…A BH3 mimetic, ABT-199, has been developed to selectively bind Bcl-2 and enhances imatinib-induced cell death in chronic myeloid leukemia progenitors (47). BDA-366, a small-molecule Bcl-2-BH4 domain antagonist, can bind BH4 of Bcl-2 with high affinity and selectivity, and this Bcl-2-BH4 antagonist may provide a strategy to improve lung cancer outcome (48).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

et al. 2017

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Abstract. Hepatocellular carcinoma (HCC) is a highly malignant tumor and can evolve rapidly to resistance to chemotherapies. Glycochenodeoxycholate (GCDA), which is toxic and hydrophobic, is the main ingredient in the bile and associated with carcinogenesis of gastrointenstinal tumors. Bcl-2 is the most important anti-apoptotic protein and overexpressed in various human tumors. In the present study, we found that GCDA can induce the chemoresistance of human liver cancer cells and specific depletion of Bcl-2 by RNA interference blocks GCDA-stimulated chemoresistance, which indicate the pivotal role of Bcl-2 in such process. Mechanistically, GCDA simultaneously stimulates phosphorylation of Bcl-2 at Ser70 site and activates extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of ERK1/2 by PD98059 (MAPK/ERK1/2 inhibitor) or siRNA (targeting ERK1/2) suppresses GCDA-stimulated phosphorylation of Bcl-2 and significantly attenuates the survival and chemoresistance induced by GCDA in liver cancer cells. Thus, GCDA-induced survival and chemoresistance of liver cancer cells may occur through activation of Bcl-2 by phosphorylation at Ser70 site through MAPK/ERK1/2 pathway, which may contribute to the development of human liver cancer and chemoresistance.

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“…Although single treatment with GEM or AgNPs induced generation of ROS, AgNPs induced significantly higher levels compared with those induced by GEM ( Figure 7A); this is consistent with previous reports demonstrating that AgNPs induce pronounced cytotoxicity in various types of cancer cells including human breast, ovarian, lung, and germ cells. 24,25,29,60,61 Interestingly, N-acetyl cysteine was able to significantly decrease the levels of ROS that had been induced by GEM, AgNPs, or a combination of GEM and AgNPs, indicating that production of ROS plays a critical role in GEM-and AgNP-induced cytotoxicity. Kovacs et al 31 demonstrated that osteosarcoma cells treated with 20 μM AgNPs (5 nm) and 85 μM AgNPs (35 nm) produced considerable levels of ROS; this study additionally confirmed that mitochondrial dysfunction is coupled to oxidative stress.…”

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confidence: 99%

Silver nanoparticles enhance the apoptotic potential of gemcitabine in human ovarian cancer cells: combination therapy for effective cancer treatment

Yuan¹,

Peng²,

Gurunathan³

2017

IJN

127

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Background Gemcitabine (GEM) is widely used as an anticancer agent in several types of solid tumors. Silver nanoparticles (AgNPs) possess unique cytotoxic features and can induce apoptosis in a variety of cancer cells. In this study, we investigated whether the combination of GEM and AgNPs can exert synergistic cytotoxic effects in the human ovarian cancer cell line A2780. Methods We synthesized AgNPs using resveratrol as a reducing and stabilizing agent. The synthesized nanomaterials were characterized using various analytical techniques. The anticancer effects of a combined treatment with GEM and AgNPs were evaluated using a series of cellular assays. The expression of pro- and antiapoptotic genes was measured using real-time reverse transcription polymerase chain reaction. Apoptosis was confirmed by TUNEL assay. Results In this study, combined treatment with GEM and AgNPs significantly inhibited viability and proliferation in A2780 cells. Moreover, the levels of apoptosis in cells treated with a combination of GEM and AgNPs were significantly higher compared with those in cells treated with GEM or AgNPs alone. Our data suggest that GEM and AgNPs exhibit potent apoptotic activity in human ovarian cancer cells. Combined treatment with GEM and AgNPs showed a significantly higher cytotoxic effect in ovarian cancer cells compared with that induced by either of these agents alone. Conclusion Our study demonstrated that the interaction between GEM and AgNPs was cytotoxic in ovarian cancer cells. Combined treatment with GEM and AgNPs caused increased cytotoxicity and apoptosis in A2780 cells. This treatment may have therapeutic potential as targeted therapy for the treatment of ovarian cancer. To our knowledge, this study could provide evidence that AgNPs can enhance responsiveness to GEM in ovarian cancer cells and that AgNPs can potentially be used as chemosensitizing agents in ovarian cancer therapy.

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Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy

Cited by 110 publications

References 59 publications

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

Silver nanoparticles enhance the apoptotic potential of gemcitabine in human ovarian cancer cells: combination therapy for effective cancer treatment

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