<p>Fenofibrate potentiates chemosensitivity to human breast cancer cells by modulating apoptosis via AKT/NF-&kappa;B pathway</p>

Abstract

BackgroundCumulatively, evidences revealed that fenofibrate used in the therapy of hyperlipidemia and hypercholesterolemia has anti-cancer effect in multiple cancer types. However, its function and underlying mechanism of chemosensitization in breast cancer remain poorly understood.Materials and methodsThe cytotoxicity of fenofibrate and anti-cancer drugs in breast cancer cells was determined by MTT. Apoptosis and mitochondrial membrane potential were measured using flow cytometry. Caspases and PARP cleavage, the Bcl-2 family members’ protein expression, as well as the activation of AKT and NF-κB signaling pathways were evaluated using Western blot assay. Real-time PCR was used to determine the mRNA expression of Bcl-2 family members.ResultsOur data indicated that fenofibrate suppressed SKBR3 and MDA-MB-231 cell growth in a dose-dependent manner, in the same way as paclitaxel, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ABT-737, and doxorubicin. Subtoxic levels of fenofibrate significantly augmented paclitaxel, TRAIL, ABT-737, and doxorubicin-induced apoptosis in both these two cell lines. Fenofibrate-promoted chemosensitivity is predominantly mediated by caspase-9 and caspase-3 activation and mitochondrial outer membrane permeabilization. Meanwhile, chemosensitivity promoted by fenofibrate also increased the expression of Bax and Bok and decreased the expression of Mcl-1 and Bcl-xl. Mechanistically, fenofibrate effectively reduced the phosphorylation levels of AKT and NF-κB. In addition, imiquimod, an NF-κB activator, could reverse fenofibrate-induced susceptibility to ABT-737-triggered apoptosis.ConclusionThe present study provided the evidence of the underlying mechanisms on chemosensitization of fenofibrate by inducing the apoptosis of breast cancer in an AKT/NF-κB-dependent manner and implicated the potential application of fenofibrate in potentiating chemosensitivity in breast cancer therapy.

PPAR-α Modulators as Current and Potential Cancer Treatments

“…Meanwhile, the study has indicated that the activation of caspase-9 and caspase-3 and the permeabilization of mitochondrial outer membrane affect fenofibrate-elevated chemosensitivity. Moreover, the synergistic effects of fenofibrate with paclitaxel, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ABT-737, and doxorubicin significantly augment chemosensitivity to enhance the apoptosis of breast cancer cells ( 72 ). Basing on the emerging evidence, fenofibrate is a promising candidate in breast cancer treatments.…”

Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis

“…Fenofibrate activates peroxisome proliferator-activated receptors α (PPARα), a transcription factor that stimulates the beta-oxidation of fatty acids ( Schoonjans et al, 1996 ). It has been found to reduce cellular proliferation and boost apoptosis in cancer cells ( Yamasaki et al, 2011 ; Sun et al, 2019 ). Since cholesterol-lowering drugs can modulate proliferation, migration, and invasion and inhibit tumorigenesis, this review article will discuss the effects of these drugs in correlation with Akt signaling.…”

“…Fenofibrate, a non-statin cholesterol lowering drug is used in the therapy of hyperlipidemia and hypercholesterolemia. It is reported to act on Akt/NF-κB pathway and reduce the phosphorylated Akt and NF-κB p65 in SKBR3 and MDA-MB-231 cells ( Sun et al, 2019 ). Akt/NF-κB pathway in breast cancer blocks the activity of pro-apoptotic genes such as Bok, Bax and BIM ( Bentires-Alj et al, 2001 ; Inta et al, 2006 ).…”

Genome-wide RNA-sequencing dataset reveals the prognostic value and potential molecular mechanisms of lncRNA in non-homologous end joining pathway 1 in early stage Pancreatic Ductal Adenocarcinoma

“…A literature review revealed that fenofibrate has anticancer effects in many malignancies, including pancreatic cancer [38], lung adenocarcinoma [39], hepatocellular carcinoma [40], melanoma [41], glioblastoma [42,43], oral cancer [44,45], prostate cancer [46,47], breast cancer [48], neuroblastoma [49], and angiosarcomas [50]. Fenofibrate also increases the sensitivity of esophageal carcinoma [51,52] and head and neck squamous cell carcinoma [37] to radiotherapy, and that of breast cancer to chemotherapy [36]. Exisulind is widely reported to have anticancer effects in a variety of malignancies, including non-small cell lung cancer [53], colon cancer [54][55][56][57][58], prostate cancer [59], breast cancer [60], head and neck squamous cell carcinoma [61], and pan-cancer [62].…”

“…NU1025 is involved in regulating the sensitivity of human cervical cancer HeLa cells to the triazoloacridone compound c-1305 through the p53 pathway, thereby synergistically participating in tumor inhibition 34 . Fenofibrate has anticancer effects in a variety of cancers 35 , and it increases the sensitivity of tumors to chemotherapy and radiotherapy 36 , 37 . A literature review revealed that fenofibrate has anticancer effects in many malignancies, including pancreatic cancer 38 , lung adenocarcinoma 39 , hepatocellular carcinoma 40 , melanoma 41 , glioblastoma 42 , 43 , oral cancer 44 , 45 , prostate cancer 46 , 47 , breast cancer 48 , neuroblastoma 49 , and angiosarcomas 50 .…”