Expression of ornithine decarboxylase in peripheral blood mononuclear cells from patients with pancreatic adenocarcinoma: A preliminary report.

Ductal adenocarcinoma represents 90-95% of pancreatic cancer (PC) cases and it is an aggressive disease with asymptomatic evolution at early stages, non-specific symptoms and a typical late diagnosis with a 5-year survival rate estimated to be 8%. A window of opportunity lies in early diagnosis as there are currently no reliable biomarkers. CA 19-9 is one of the most frequently used biomarkers of PC, with 75 and 77.6% sensitivity (Se) and specificity (Sp), respectively, and the carcinoembryonic antigen (CEA) shows 39.5 and 81.3% of Se and Sp, respectively. A case-control study was conducted including adult patients with a histological diagnosis of PC (n=11) without previous treatment at the Oncology Service of the CMNO-IMSS between 2019 and 2020, and a control group of adult volunteers (n=11) who were clinically healthy or with controlled disease including hypertension, hypothyroidism and diabetes. Clinical, laboratory and sociodemographic data as well as blood, urine and saliva samples were collected following patient consent. Polyamines were quantified using high-performance liquid chromatography with fluorescence detection, CA 19-9 and CEA were evaluated using enzyme-linked immunosorbent assay, and the protein expression of ornithine decarboxylase (ODC) was evaluated using western blotting. Polyamine metabolism and modulation by means of ODC were increased in the serum and saliva of patients with PC, and the expression of ODC alone was increased in peripheral blood mononuclear cells (PBMCs). The present study focused on the evaluation of putrescine, spermine, spermidine and ODC in PBMCs associated with CA 19-9 and CEA as an auxiliary tool in PC diagnosis.

Pentoxifylline Inhibits TNF-α/TGF-ß1-Induced Epithelial-Mesenchymal Transition via Suppressing the NF-κB Pathway and SERPINE1 Expression in CaSki Cells.

Cervical cancer (CC) is one of the most common and deadly types of female cancer worldwide. Late diagnosis in CC increases the risk of tumor cells spreading to distant organs (metastasis). The epithelial-mesenchymal transition (EMT) is a fundamental process of cancer metastasis. Inflammation can lead to tumor progression, EMT induction, and metastasis. The inflammatory microenvironment is a potent inducer of EMT; inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Transforming growth factor-beta (TGF-ß1) activate transcriptional factors such as STAT3, Snail, Smad, and the Nuclear Factor kappa light-chain-enhancer of activated beta cells (NF-κΒ), which drive EMT. Anti-inflammatory compounds may be an option in the disruption of EMT. PenToXifylline (PTX) possesses potent anti-inflammatory effects by inhibiting NF-κB activity. In addition, PTX exerts an anti-fibrotic effect by decreasing Smad2/3/4. We hypothesize that PTX could exert anti-EMT effects. CaSki human cervical tumor cells were exposed to TNF-α 10 ng/mL and TGF-ß1 alone or in combination for 5 days. Our results revealed that TNF-α and TGF-ß1 induced N-cadherin and Vimentin, confirming the induction of EMT. Furthermore, the combination of cytokines synergized the expression of mesenchymal proteins, enhanced IκBα and p65 phosphorylation, and upregulated Serpin family E member 1 (SERPINE1) mRNA. PTX pretreatment prior to the addition of TNF-α and TGF-ß1 significantly reduced N-cadherin and Vimentin levels. To our knowledge, this is the first time that this effect of PTX has been reported. Additionally, PTX reduced the phosphorylation of IκB-α and p65 and significantly decreased SERPINE1 expression, cell proliferation, migration, and invasion. In conclusion, PTX may counteract EMT in cervical cancer cells by decreasing the NF-κB and SERPINE1.

Sensitizing the cytotoxic action of Docetaxel induced by Pentoxifylline in a PC3 prostate cancer cell line.

BACKGROUND: Prostate cancer is one of the most frequently diagnosed types of cancers worldwide. In its initial period, the tumor is hormone-sensitive, but in advanced states, it evolves into a metastatic castration-resistant tumor. In this state, chemotherapy with taxanes such as Docetaxel (DTX) comprises the first line of treatment. However, the response is poor due to chemoresistance and toxicity. On the other hand, Pentoxifylline (PTX) is an unspecific inhibitor of phosphodiesterases; experimental, and clinically it has been described as sensitizing tumor cells to chemotherapy, increasing apoptosis and decreasing senescence. We study whether the PTX sensitizes prostate cancer cells to DTX for greater effectiveness. METHODS: PC3 human prostate cancer cells were treated in vitro at different doses and times with PTX, DTX, or their combination. Viability was determined by the WST-1 assay by spectrophotometry, cell cycle progression, apoptosis, generic caspase activation and senescence by flow cytometry, DNA fragmentation and caspases-3, -8, and -9 activity by ELISA. RESULTS: We found that PTX in PC3 human prostate cancer cells induces significant apoptosis per se and increases that generated by DTX, while at the same time it reduces the senescence caused by the chemotherapy and increases caspases-3,-8, and -9 activity in PTX + DTX-treated cells. Both treatments blocked the PC3 cell in the G1 phase. CONCLUSIONS: Our results show that PTX sensitizes prostate tumor cells to apoptosis induced by DTX. Taken together, the results support the concept of chemotherapy with rational molecular bases.

Pentoxifylline Enhances the Apoptotic Effect of Carboplatin in Y79 Retinoblastoma Cells.

BACKGROUND/AIM: Retinoblastoma (RB) is the most common primary intraocular malignancy. Carboplatin (CPt) is a DNA damage-inducing agent that is widely used for the treatment of RB. Unfortunately, this drug also activates the transcription factor nuclear factor-kappa B (NF-ĸB), leading to promotion of tumor survival. Pentoxifylline (PTX) is a drug that inhibits the phosphorylation of I kappa B-alpha (IĸBα) in serines 32 and 36, and this disrupts NF-ĸB activity that promotes tumor survival. The goal of this study was to evaluate the effect of the PTX on the antitumor activity of CPt. MATERIALS AND METHODS: Y79 RB cells were treated with CPt, PTX, or both. Cell viability, apoptosis, loss of mitochondrial membrane potential, the activity of caspase-9, -8, and -3, cytochrome c release, cell-cycle progression, p53, and phosphorylation of IĸBα, and pro- and anti-apoptotic genes were evaluated. RESULTS: Both drugs significantly affected the viability of the Y79 RB cells in a time- and dose-dependent manner. The PTX+CPt combination exhibited the highest rate of apoptosis, a decrease in cell viability and significant caspase activation, as well as loss of mitochondrial membrane potential, release of cytochrome c, and increased p53 protein levels. Cells treated with PTX alone displayed decreased I kappa B-alpha phosphorylation, compared to the CPt treated group. In addition, the PTX+CPt combination treatment induced up-regulation of the proapoptotic genes Bax, Bad, Bak, and caspases- 3, -8, and -9, compared to the CPt and PTX individual treated groups. CONCLUSION: PTX induces apoptosis per se and increases the CPt-induced apoptosis, augmenting its antitumor effectiveness.

Dysregulation of the Th1/Th2 cytokine profile is associated with immunosuppression induced by hypothalamic-pituitary-adrenal axis activation in mice.

Hypothalamic-pituitary-adrenal (HPA) axis activation-induced immunosuppression is associated with increased concentration of circulating corticosterone and impaired cellular immune responses. The purpose of this study was to investigate the effect of chronic HPA axis activation on the cellular immune response, Th1/Th2 cytokine profile, and concentration of corticosterone. Mice were divided into two groups: a control group comprised of healthy, untreated mice that received no stress, and an HPA axis-activated group that received stress through electric shock (ES). The delayed-type hypersensitivity reaction to dinitrofluorobenzene, splenocyte proliferative response to mitogens Concanavalin A and lipopolysaccharide, Th1 and Th2 profile, and TGF-beta1 production were measured in plasma and in culture supernatants. The corticosterone concentration was also measured in plasma. In the ES group, elevated plasma corticosterone concentration was associated with immunosuppression and a significant decrease in plasma concentrations of IL-2, IL-4, and TGF-beta1. In vitro IL-2 production in response to Con A was significantly lower in the ES group than in the control group. TGF-beta1 production in nonstimulated and stimulated cultures in response to either mitogen was significantly lower in the ES group than in the control group. Plasma concentrations of IFN-gamma and IL-10 did not differ significantly between groups. The concentrations of IFN-gamma, IL-4, and IL-10 in the supernatants of splenocytes stimulated with either mitogen and IL-4 production by nonstimulated cells were significantly higher in the ES group than in the control group. These results suggest that corticosterone mediates the immunosuppression induced by HPA axis activation, and induces dysregulation of the Th1/Th2 cytokine profile.

Effect of Ginkgo biloba extract EGb 761 on the nonspecific and humoral immune responses in a hypothalamic-pituitary-adrenal axis activation model.

We evaluated the immune response of healthy control and stressed Wistar rats submitted to hypothalamic-pituitary-adrenal (HPA) axis activation. Rats were treated with Ginkgo biloba extract (EGb 761) orally (100 mg/kg per day for 7 days). EGb 761 stimulated the digestion index of peritoneal and alveolar macrophages (PM and AM) of stressed rats. Likewise, the cellular immune response measured using the delayed-type hypersensitivity response to sheep red blood cells (SRBC) and the humoral immune response (measured through an anti-SRBC response), were also restored in stressed rats. Thus, this G. biloba extract possesses immunostimulatory activity in addition to its broad spectrum of pharmacological effects.

Effect of Ginkgo biloba extract, EGb 761, on the cellular immune response in a hypothalamic-pituitary-adrenal axis activation model in the rat.

We evaluated the effects of Ginkgo biloba extract (EGb 761) on the cellular immune response of rats with immunosuppression induced by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Groups of five rats were subjected to chronic stress by the application of daily electric shocks (ES) over 7 days. This stress produced a significant decrement in the delayed-type hypersensitivity response (DTH) to dinitrofluorobenzene (DNFB), and a decrease in the proliferation index of splenocytes. Treatment with oral doses of the phytopharmaceutical EGb 761 (100 mg/kg per day over 7 days) restored both the DTH response to DNFB and the proliferation index. EGb 761 has stress-alleviating properties through its moderation of corticosterone levels. It also possesses antioxidant activity that may contribute to its effects on the immune response. Our observations indicate that the phytopharmaceutical EGb 761 possesses immunostimulatory properties.