Curcumin is assumed to be a plant-derived therapeutic drug that triggers apoptotic cell death in vitro and in vivo by affecting different molecular targets such as NF-κB. Phase I/II trial of curcumin alone or with chemotherapeutic drugs has been accomplished in pancreatic, colon, prostate and breast cancer cases. Recently, autocrine growth hormone (GH) signaling-induced cell growth, metastasis and drug resistance have been demonstrated in breast cancer. In this study, our aim was to investigate the potential therapeutic effect of curcumin by evaluating the molecular machinery of curcumin-triggered apoptotic cell death via focusing on NF-κB signaling and polyamine (PA) metabolism in autocrine GH-expressing MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells. For this purpose, a pcDNA3.1 (+) vector with a GH gene insert was transfected by a liposomal agent in all breast cancer cells and then selection was conducted in neomycin (G418) included media. Autocrine GH-induced curcumin resistance was overcome in a dose-dependent manner and curcumin inhibited cell proliferation, invasion-metastasis and phosphorylation of p65 (Ser536), and thereby partly prevented its DNA binding activity in breast cancer cells. Moreover, curcumin induced caspase-mediated apoptotic cell death by activating the PA catabolic enzyme expressions, which led to generation of toxic by-products such as HO in MCF-7, MDA-MB-453 and MDA-MB-231 GH+ breast cancer cells. In addition, transient silencing of SSAT prevented curcumin-induced cell viability loss and apoptotic cell death in each breast cancer cells. In conclusion, curcumin could overcome the GH-mediated resistant phenotype via modulating cell survival, death-related signaling routes and activating PA catabolic pathway.

The mortality rate of pancreatic cancer has close parallels to its incidence rate because of limited therapeutics and lack of effective prognosis. Despite various novel chemotherapeutics combinations, the 5‐year survival rate is still under 5%. In the current study, we aimed to modulate the aberrantly activated PI3K/AKT pathway and epithelial‐mesenchymal transition (EMT) signaling with the treatment of CDK4/6 inhibitor PD‐0332991 (palbociclib) in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells. It was found that PD‐0332991 effectively reduced cell viability and proliferation dose‐dependently within 24 hours. In addition, PD‐0332991 induced cell cycle arrest at the G1 phase by downregulation of aberrant expression of CDK4/6 through the dephosphorylation of Rb in each cell lines. Although PD‐0332991 treatment increased epithelial markers and decreased mesenchymal markers, the nuclear translocation of β‐catenin was not prevented by PD‐0332991 treatment, especially in MiaPaCa‐2 cells. Effects of PD‐0332991 on the regulation of PI3K/AKT signaling and its downstream targets such as GSK‐3 were cell type‐dependent. Although the activity of AKT was inhibited in both cell lines, the phosphorylation of GSK‐3β at Ser9 increased only in Panc‐1. In conclusion, PD‐0332991 induced cell cycle arrest and reduced the cell viability of Panc‐1 and MiaPaCa‐2 cells. However, PD‐0332991 differentially affects the regulation of the PI3K/AKT pathway and EMT process in cells due to its distinct influence on Rb and GSK‐3/β‐catenin signaling. Understanding the effect of PD‐0332991 on the aberrantly activated signaling axis may put forward a new therapeutic strategy to reduce the cell viability and metastatic process of pancreatic cancer.

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Pituitary adenoma is the most common tumor with a high recurrence rate due to a hormone-dependent JAK/signal transducer and activator of transcriptions (STAT) signaling. Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, has antiproliferative, anticarcinogenic effects in multiple myeloma, breast, and hepatocellular carcinoma by blocking STAT3 activation. Therapeutic agents' efficiency depends on endoplasmic reticulum (ER) stress-autophagy regulation during drug-mediated apoptotic cell death decision. However, the molecular machinery of dose-dependent atiprimod treatment regarding ER stress-autophagy has not been investigated yet. Thus, our aim is to investigate the ER stress-autophagy axis in atiprimodmediated apoptotic cell death in GH-secreting rat cell line (GH3) pituitary adenoma cells. Dose-dependent atiprimod treatment decreased GH3 cell viability, inhibited cell growth, and colony formation. Upregulation of Atg5, Atg12, Beclin-1 expressions, cleavage of LC-3II and formation of autophagy vacuoles were determined only after 1 µM atiprimod exposure. In addition, atiprimod-triggered ER stress was evaluated by BiP, C/EBP-homologous protein (CHOP), p-PERK upregulation, and Ca +2 release after 1 µM atiprimod exposure.Concomitantly, increasing concentration of atiprimod induced caspase-dependent apoptotic cell death via modulating Bcl 2 family members. Moreover, by Nacetyl cycteinc pretreatment, atiprimod triggered reactive oxygen species generation and prevented apoptotic induction. Concomitantly, dose-dependent atiprimod treatment decreased both GH and STAT3 expression in GH3 cells. In Abbreviations: AMPK, AMP-activated protein kinase; AO, acridine orange; ATF6, activating transcription factor 6; CHOP, C/EBP-homologous protein; DiOC6, 3,3′-dihexyloxacarbocyanine iodide; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid; eIF-2 α, eukaryotic initiation factor 2; HRP, horseradish peroxidase; IRE-1α, inositol-requiring protein-1α; mTOR, mammalian target of rapamycin; MTT, 3-(4,5-