Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma

Lang, Mingxiao; Wang, Xiuchao; Wang, Hongwei; Dong, Jie; Lan, Chungen; Hao, Jihui; Huang, Chongbiao; Li, Xin; Yu, Ming; Yang, Yanhui; Yang, Shengyu; Ren, He

doi:10.1016/j.canlet.2016.05.016

Cited by 30 publications

(34 citation statements)

References 49 publications

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“…The pharmacological effects of As 2 O 3 attracted more attention following promising results as treatment for acute promyelocytic leukemia (APL). The main antitumor mechanism of action of As 2 O 3 is through inducing tumor cell differentiation and apoptosis, inhibiting tumor cell proliferation and affecting the tumor neoangiogenesis (4,5,18). Our research demonstrated that As 2 O 3 inhibited the growth of tumor cells, the conversion from colorectal CSCs to CRC cells, and it increased the density of CSCs.…”

Section: Discussionmentioning

confidence: 64%

Effect of As2O3 on colorectal CSCs stained with ALDH1 in primary cell culture in�vitro

Ning¹,

Ning

et al. 2018

Oncol Lett

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Colorectal carcinoma (CRC) is one of the most common types of malignant tumor in humans, and its morbidity is on the increase in economically transitioning countries. Due to its high toxicity, the use of the Chinese Traditional Medicine arsenic (AsO) is limited. However, certain studies have reported that AsO induces differentiation of tumor cells, promotes tumor cell apoptosis and inhibits tumor cell proliferation, although the number of studies on the effects of AsO on cancer stem cells (CSCs) of CRC is limited. In order to research the effects of different concentrations of AsO on CRC cells and colorectal CSCs , aldehyde dehydrogenase 1 (ALDH1) was sued to stain the cytoplasm of colorectal CSCs and DAPI was used to stain the nuclei of all tumor cells. Through observing the effect of different concentrations of AsO on CRC cells and colorectal CSCs, it was demonstrated that a sufficient concentration of AsO clearly inhibited the conversion from colorectal CSCs to CRC cells and increased the density of CSCs.

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Section: Discussionmentioning

confidence: 64%

Effect of As2O3 on colorectal CSCs stained with ALDH1 in primary cell culture in�vitro

Ning¹,

Ning

et al. 2018

Oncol Lett

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“…reported that PX-478, a hypoxia-inducible factor-1 inhibitor, robustly strengthens the antigrowth and proapoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro by mediating ROS accumulation [51].…”

Section: Pancreatic Cancermentioning

confidence: 99%

Arsenic-Based Anticancer-Combined Therapy: Novel Mechanism Inducing Apoptosis of Cancer Cells

Ota¹,

Wahiduzzaman²,

Hosokawa³

2018

Current Understanding of Apoptosis - Programmed Cell Death

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Arsenic, known as both a naturally occurring toxic element and a traditionally used drug, has caught a great deal of attention from worldwide people due to its curable anticancer effect in patients with acute promyelocytic leukemia (APL). Among the arsenicals, arsenic trioxide (ATO) has been the most widely used anticancer drug. Since ATO exerts an anticancer effect by mediating apoptosis, numerous studies have made efforts to uncover the molecular mechanisms by which ATO activates and/or mediates the apoptotic signaling pathway in cancer cells. Recent advances in cancer therapeutics have led to a paradigm shift away from the traditional cytotoxic drugs toward the targeting of proteins closely associated with driving the cancer phenotype. Here, we discuss novel current arsenic-based combination therapies to treat cancer in both clinical and experimental settings. We also discuss the novel molecular mechanism underlying apoptosis induced by the combined therapies.

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“…PX-478 interferes with the transcription and translation of hypoxia-inducible factor-1α (HIF1α) and leads to diminished deubiquitination of HIF-1α (26), thereby inducing apoptosis and cell cycle arrest (27,28). In addition, PX-478 induces elevated levels of ROS (28). In oesophageal squamous cell cancer, PX-478 induces apoptosis and reduces cell proliferation and inhibits epithelial-mesenchymal transition (29).…”

Section: Compoundsmentioning

confidence: 99%

Dichloroacetate and PX-478 Exhibit Strong Synergistic Effects in a Various Number of Cancer Cell Lines.

Parczyk

Ruhnau

Pelz

et al. 2020

Preprint

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Background: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Further, the likelihood of drug resistance is reduced. Distinct alterations in tumour metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for a synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor and HIF1-α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms.Methods: The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using MTT or SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells.Results: The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment.Conclusions: Here, we found that these cancer metabolism-targeting compounds exhibited potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials.

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Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma

Cited by 30 publications

References 49 publications

Effect of As2O3 on colorectal CSCs stained with ALDH1 in primary cell culture in�vitro

Effect of As2O3 on colorectal CSCs stained with ALDH1 in primary cell culture in�vitro

Arsenic-Based Anticancer-Combined Therapy: Novel Mechanism Inducing Apoptosis of Cancer Cells

Dichloroacetate and PX-478 Exhibit Strong Synergistic Effects in a Various Number of Cancer Cell Lines.

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