Melatonin increases the anticancer potential of doxorubicin in Caco-2 colorectal cancer cells.

Colorectal cancer (CC) is an important human malignancy with high cancer related death worldwide. The chemotherapy using doxorubicin hydrochloride is one of the most common cancer therapeutic methods. However, drug resistance lowers the treatment efficacy in CC patients. The combination therapies seem to be more promising by taking the advantage of synergistic effects. The present study aimed to evaluate a new strategy to enhance the anticancer activity of doxorubicin in Caco-2 CC cell line by co-administration of melatonin. The effects of doxorubicin, melatonin, and their combinations (Dox-Mel) were investigated on the proliferation and viability, morphological alterations, and tumor spheroid formation. Flow cytometry was employed to compare the apoptotic situation of the cells in study groups. Changes in metastatic potential of the cells were assessed by wound healing assay and trans-well migration assays. Moreover, expression of BAX, SMAC, BCL-2, SURVIVIN, MMP-2, and MMP-9 genes were evaluated by quantitative real time PCR and western blotting. Our study showed that doxorubicin, melatonin, and Dox-Mel significantly decreased the proliferation and viability, tumor spheroid formation, invasion, and migration. Furthermore, the changes were in a concentration and time dependent manner. There was an increase in apoptosis rate in the treatment groups. Expression of genes involved in apoptosis and cell motility were altered significantly. It was observed that anticancer activity of Dox-Mel combination was significantly more than doxorubicin and melatonin treatments alone. We showed an enhanced apoptotic and anticancer activity of doxorubicin and melatonin combination chemotherapy on CC cell line than doxorubicin or melatonin treatments alone. This combination could promote the treatment efficiency and alleviate the un-intended side effects by lowering the dose of doxorubicin prescription.

Enhanced anticancer potency of hydroxytyrosol and curcumin by PLGA-PAA nano-encapsulation on PANC-1 pancreatic cancer cell line.

Many chemotherapeutic regimens have been investigated for advanced unresectable and metastatic pancreatic cancer (PC), but with only minimal improvement in survival and prognosis. Here, we investigated anti-cancer function of free and nano-encapsulated hydroxytyrosol (Hyd) and curcumin (Cur), and its combinations (Hyd-Cur) on PANC-1 cell line. The poly lactide-co-glycolide-co-polyacrylic acid (PLGA-co-PAA) nano-encapsulated Hyd and Cur were synthesized, and MTT assay was performed to evaluate cytotoxic effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur. Effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur were evaluated on viability, migration, morphological alterations, colony formation, and apoptosis on PANC-1 cells. We observed that free and nano-encapsulated Hyd, Cur, and Hyd-Cur significantly increased apoptosis rates as well as significantly decreased viability, migration, and colony formation in PANC-1 cells. According to our results, Hyd-Cur combination and nano-encapsulation therapy exerts more profound apoptotic and anti-proliferative effects on PANC-1 cells than free Hyd or Hyd monotherapy.

Resistance mechanisms to immune checkpoints blockade by monoclonal antibody drugs in cancer immunotherapy: Focus on myeloma.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of neoplastic proliferation of a plasma cell in the bone marrow that produces a monoclonal immunoglobulin. The immune checkpoint inhibitors against programmed death-1/programmed death-1 ligand and cytotoxic T-lymphocyte antigen 4 axis have demonstrated appropriate anticancer activity in several solid tumors and liquid cancers, and are rapidly transforming the practice of medical oncology. However, in a high percentage of patients, the efficacy of immune checkpoints blockade remains limited due to innate or primary resistance. Moreover, the malignancies progress in many patients due to acquired or secondary resistance, even after the clinical response to immune checkpoints' blockade. The evidence shows that multiple tumor-intrinsic and tumor-extrinsic factors and alterations in signaling pathways are involved in primary and secondary resistance to immune checkpoints blockade. Improved identification of intrinsic and extrinsic factors and mechanisms of resistance or response to immune checkpoints blockade may not only provide novel prognostic or predictive biomarkers but also guide the optimal combination/sequencing of immune checkpoint blockade therapy in the clinic. Here, we review the underlying biology and role of immune checkpoints blockade in patients with MM. Furthermore, we review the host and tumor-related factor effects on immune checkpoints blockade in MM immunotherapy.

Association of IL-33 gene rs16924159 polymorphism and recurrent pregnancy loss in Iranian Azeri women.

BACKGROUND: Recurrent pregnancy loss (RPL) referred to two or more consecutive abortions before 20th week of pregnancy. The imbalance of inflammatory factors such as interleukins (IL) can be a significant factor in the RPL. The aim of this study was to investigate association of interleukin-33 (IL-33) gene rs16924159 polymorphism and RPL in Iranian Azeri women. MATERIALS AND METHODS: This case-control study consisted of 100 women with RPL as case group and 100 healthy controls with successful delivery. Genomic DNA was extracted from whole blood samples using salting out method. The fragments of the rs16924159 polymorphism were amplified by PCR and the genotyping was performed using DNA sequencing. RESULTS: The obtained results showed that frequency of GA genotype and G allele of rs16924159 polymorphism in the case group was significantly more than healthy controls (p = 0.033). CONCLUSIONS: Generally, we showed that the IL-33 gene rs16924159 polymorphism may play an important role in risk of RPL in the Iranian Azeri women. However, further studies on different races and geographic areas can be useful in identification of effects of rs16924159 polymorphism on RPL.

Association of nitric oxide synthase 3 gene rs1799983 G/T polymorphism with idiopathic asthenozoospermia in Iranian Azeri males: a case-control study.

OBJECTIVES: Recently, oxidative stress (OS) has been described extensively as an important cause of men infertility. The nitric oxide synthase 3 (NOS3) gene expression involved in normal spermatogenesis regulation in testis. Several single nucleotide polymorphisms (SNPs) on NOS3 gene are reported in association with sperm function and spermatogenesis impairment in infertile men. In present study, we investigated association of NOS3 gene rs1799983 G/T polymorphism in Iranian Azeri male with idiopathic asthenozoospermia (AZS). METHODS: In this case-control study, we collected 50 males with idiopathic AZS as a case group and 50 age and ethnically matched male as healthy controls from East Azerbaijan area, Iran. The case and control groups genotyping was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction (Tetra-ARMS PCR) method. RESULTS: Genotype frequency in AZS patients was 40% GG, 60% GT, and 0% TT, whereas in healthy controls were 60% GG, 30% GT, and 10% TT. Statistical analysis showed that the GT heterozygous genotype frequency of NOS3 gene rs1799983 G/T polymorphism in AZS patients was significantly more than healthy controls (p>0.05). CONCLUSIONS: We demonstrated that NOS3 gene rs1799983 G/T polymorphism was associated with AZS in Iranian Azeri men. However, more studies on different geographic areas, races and ethnicities are required to determine exact role of NOS3 gene rs1799983 G/T polymorphism in idiopathic AZS.