Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer

Wang

et al. 2018

Cell Physiol Biochem

Background/Aim: Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL)-based therapies have been used in many human cancers. However, some tumors are resistant to TRAIL-induced cell death. Aldehyde dehydrogenase 1 (ALDH1) is a functional marker for identification of CSCs. Methods: In this study, we used the colony formation assay, AnnexinV/ PI double staining and PI staining to detect proliferation, apoptosis and cell cycle in ALDH1⁺ non-small cell lung cancer (NSCLC) cells with TRAIL treatment. In addition, we established xenograft mouse models to confirm the anti-tumor roles of TRAIL in vivo. Finally, gene array and western blot were used to detect the deeper mechanism of the susceptibility of ALDH1⁺ NSCLC cells to TRAIL. Results: We confirmed that TRAIL could inhibit proliferation, and induce apoptosis and G₁ arrest in ALDH1⁺ NSCLC cells. Correspondingly, TRAIL was associated with decreased tumor size and the favorable survival rate of ALDH1⁺ cells established xenograft mouse models. ALDH1 could increase the death receptors (DR) 4 and DR5 expression in ALDH1⁺ NSCLC cells via activating MEK/ERK signaling pathway. Conclusion: ALDH1 protein induced MEK-1 mRNA stability and promoted its translation via its 3’UTR.

Section: Discussionsupporting

confidence: 57%

Aldehyde Dehydrogenase 1 (ALDH1) Promotes the Toxicity of TRAIL in Non-Small Cell Lung Cancer Cells via Post-Transcriptional Regulation of MEK-1 Expression

Shen

Wang

et al. 2018

Cell Physiol Biochem

“…Several kinds of strategy have been carried out to reverse Dox resistance in breast cancer according to its corresponding mechanism, including developing chemosensitizers, improving drug delivery systems, modulating drug resistance‐related signaling pathways, and etc. Among these strategies, chemosensitizers are the earliest and most studied; however, most of the chemosensitizers either necessitate higher doses or increase their blood drug concentration while increasing the chemotherapeutic drugs concentration in tumor cells, thereby causing serious toxic side effects (Bates et al, ; Ozols et al, ); therefore, they cannot be widely used in clinic; though improving drug delivery systems can increase chemotherapeutic drugs concentration in tumor cells (Chen et al, ; Zhong et al, ), it cannot be widely used in clinic because it cannot reduce the toxic side effects caused by high concentration of chemotherapeutic drugs; though regulating drug resistance‐related signaling pathways can reverse tumor cells resistance (Awasthi, Monahan, Stefaniak, Schwarz, & Schwarz, ; Yang et al, ), it also can cause the dysfunction of the corresponding signaling pathway in normal cells; therefore, regulating drug resistance‐related signaling pathways to reverse tumor cells resistance also cannot widely be used in clinic. Though Dox is the first‐line drug for breast cancer chemotherapy, it is currently usually used in combination with one or two chemotherapeutic drugs, which may achieve better therapeutic effects while accumulating the toxic side effects of other chemotherapeutic drugs, thereby may affect the life quality of breast cancer patients and even limit the clinical application of chemotherapy (Veronese et al, ).…”

Section: Discussionmentioning

confidence: 99%

Combination of tanshinone IIA and doxorubicin possesses synergism and attenuation effects on doxorubicin in the treatment of breast cancer

Li¹,

Zhao³

et al. 2019

Phytotherapy Research

Doxorubicin (Dox) is a first‐line drug for breast cancer chemotherapy. However, with the prolongation of chemotherapy cycle, breast cancer cells are increasingly tempt to resist Dox, and meanwhile, high cumulative dose of Dox brings enhancing toxic side effects, and these effects may lead to chemotherapy failure. Hence, it is necessary to search an agent in combination medication with Dox, which can not only enhance the chemosensitivity of Dox but also reduce the toxic side effects. Tanshinone IIA (Tan IIA) is reported to have antitumor activity in addition to its cardiovascular protective effects. We employed human breast cancer MCF‐7 and MCF‐7/dox cells in order to assess whether Tan IIA might perform such function. Our in vitro studies showed that Tan IIA could enhance the sensitivity of breast cancer cells to Dox through inhibiting the PTEN/AKT pathway and downregulating the expression of efflux ABC transporters including P‐gp, BCRP, and MRP1. In addition, our in vivo studies showed Tan IIA enhanced the chemotherapeutic effect of Dox against breast cancer while reducing its toxic side effects including weight loss, myelosuppression, cardiotoxicity, and nephrotoxicity. Therefore, Tan IIA could be used as a novel agent combined with Dox in breast cancer therapy.

“…Numerous studies have shown that specific molecules can affect the tumorigenesis, progression, incursion as well as migration of pancreatic cancer by participating in the regulation of JAK/STAT pathway . MAPKKK cascade is the key molecule in the MAPK pathway, and MAPK pathway can be incorporated to control cell propagation, invasion, migration, apoptosis, tumorigenesis, and progression of pancreatic tumor, as well as chemotherapy response and clinical outcomes . For the two drugs that were identified in our current study, no previous studies have identified their functions on cancer treatment.…”

Section: Discussionmentioning

confidence: 88%

“…[41][42][43][44] MAPKKK cascade is the key molecule in the MAPK pathway, and MAPK pathway can be incorporated to control cell propagation, invasion, migration, apoptosis, tumorigenesis, and progression of pancreatic tumor, as well as chemotherapy response and clinical outcomes. [45][46][47][48][49][50][51] For the two drugs that were identified in our current study, no previous studies have identified their functions on cancer treatment. These two drugs as the targeted agents for pancreatic cancer remain to be confirmed by further research as well as clinical trials.…”

Section: Discussionmentioning

confidence: 96%

Identify potential clinical significance of long noncoding RNA forkhead box P4 antisense RNA 1 in patients with early stage pancreatic ductal adenocarcinoma

Chen

et al. 2020

Cancer Medicine

Previous studies have shown that forkhead box P4 antisense RNA 1 (FOXP4‐AS1) is dysregulated in tumor tissues and can serve as a prognostic indicator for multiple cancers. However, the clinical significance of FOXP4‐AS1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The goal of this study is to recognize the possible clinical significance of long noncoding RNA FOXP4‐AS1 in patients with early stage PDAC. A total of 112 patients from The Cancer Genome Atlas (TCGA) PDAC cohort, receiving RNA sequencing, were involved in the study. Survival analysis, functional mechanism, and potential small molecule drugs of target therapy of FOXP4‐AS1 were performed in this study. Survival analysis in TCGA PDAC cohort suggested that patients with high FOXP4‐AS1 expression had significantly augmented possibility of death than in PDAC patients with lower FOXP4‐AS1 expression (adjusted P = .008; adjusted HR = 2.143, 95% CI = 1.221‐3.760). In this study, a genome‐wide RNA sequencing dataset was used to identify 927 genes co‐expressing with FOXP4‐AS1 in PDAC tumor tissues. A total of 676 differentially expressed genes were identified between different FOXP4‐AS1 expression groups. Functional enrichment analysis of these genes and gene set enrichment analysis for PDAC genome‐wide RNA sequencing dataset was done. We have found that FOXP4‐AS1 may function in PDAC by participating in biological processes and pathways including oxidative phosphorylation, tricarboxylic acid cycle, classical tumor‐related pathways such as NF‐kappaB as well as Janus kinase/signal transducers in addition to activators of transcription, cell proliferation, and adhesion. In addition, we also screened two potential targeted therapeutic small molecule drugs (dimenhydrinate and metanephrine) for FOXP4‐AS1 in PDAC. In conclusion, our present study demonstrated that higher expression of FOXP4‐AS1 in PDAC tumor tissues were related with an inferior medical outcome. Through multiple genome‐wide approaches, we identified the potential molecular mechanisms of FOXP4‐AS1 in PDAC and two targeted therapeutic drugs for it.