الفهرس 
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Abstract
Globally, prostate cancer is one of the major, usually occurring cancers in males and is considered the second cause of cancer-mediated death, regardless of the advancements in treatment of localized stage of prostate cancer, the major cause of mortality in prostate cancer is still attributed to the recurrence and transition to metastatic castration-resistant prostate cancer.
Tramadol is an opioid analgesic drug with multiple analgesic synergistic mechanisms, acting via obstructing the reabsorption of neurotransmitter like serotonin and norepinephrine as well as activating the mu-opioid receptors. Ketamine is a non-competitive blocker of nonsteroidal receptors and is the only intravenous anaesthetic with definite analgesic effects. It interacts with multiple binding sites including opioid receptors ( preferably) mu receptors, N-methyl-D-aspartate receptors (NMDA), and calcium channels.
Drug repurposing or reprofiling refers to discovering novel clinical benefits of preapproved drugs with established drug characteristics (including efficacy, pharmacodynamics, pharmacokinetics and toxicity) which are already used for treating other diseases, hence, reducing time and cost of the research process for a putative anticancer drug. Drug combination is defined as utilizing a blend of ≥ 2 medications, preferably, having different mechanisms of action and targeted goals to participate simultaneously in affecting various oncologic pathways.
Upon miscellaneous insults, cell death may take place through either unprogrammed, accidental process, or programmed regulated process which was subclassified according to morphological characteristics and molecular mechanisms into 12 subtypes; (i) extrinsic apoptosis (ii) intrinsic apoptosis (iii) necroptosis (iv) parthanatos (v) autophagy-dependent cell death (vi) pyroptosis, (vii) ferroptosis (viii) entotic cell death (ix) NETotic cell death (x) lysosome-dependent cell death (xi) mitochondrial permeability transition (MPT)-driven necrosis (xii) immunogenic cell death.
The present study investigated the repurposing of tramadol and ketamine as monotherapy and in combination as potential anticancer medications for human prostate cancer cells PC3 and DU145.
Applying real-time PCR, The anticancer effects of tramadol and/ or ketamine on PC3 and DU145, were evaluated by studying genes’ expression related to apoptosis (TNFRSF10A), autophagy (ATG3, Beclin1), necroptosis (RIPK1), parthanatos (PARP1), mitogen-activated protein kinase pathway (Raf1/MEK2/ERK1), endoplasmic reticulum-stress (IRE1, ATF6) and epithelial–mesenchymal transition (E-cadherin, N-cadherin) pathways.
PC3 cells, untreated serving as control, PC3 cells treated with 1.0 mM of TRA, PC3 cells treated with 1.0 mM of KET and PC3 cells treated with (1.0 mM TRA + 1.0 mM KET). As well as DU145 cells, untreated serving as control, DU145 cells treated with
0.3 mM of TRA, DU145 cells treated with 0.3 mM of KET and DU145 cells treated with (0.3 mM TRA + 0.3 mM KET).
The molecular studies revealed that, in tramadol-treated PC3 cells, there were statistically significant increase in expression of all 12 genes involved except E-cadherin, while In ketamine-treated PC3 cells, there were significant increase in all genes involved except ERK1, IRE1, ATF6, E-cadherin and N-cadherin. while in combined-treated PC3 cells, there were significant increase in all genes involved except ATF6, E-cadherin and
N-cadherin. On the other hand, In tramadol- treated DU145 cells, there were statistically significant increase in PARP1 and IRE1 but insignificant increase in the other genes, also, in ketamine- treated DU145 cells, there were significant increase in ATG3, Beclin1 and ATF6 only, whereas, in combined-treated DU145 cells, there were significant increase in N-cadherin. while there were insignificant increase in the other genes.
As observed, PC3 cells was more responsive to the treatment than DU145 cells, which may be due to variations in mechanisms of action of tramadol and ketamine, as well as the difference in aggressiveness and proliferation nature of both cells.
Tramadol and /or ketamine are candidates for combination therapy, especially for PC3 cells, and are a promising treatment strategy for prostate cancer. Further studies are recommended on various cell lines using different concentrations of tramadol and/or ketamine for different durations.