Cancer comprises a group of heterogeneous diseases encompassing high rates of morbidity and mortality. Heterogeneity, which is a hallmark of cancer, is one of the main factors related to resistance to chemotherapeutic agents leading to poor prognosis. Heterogeneity is profoundly affected by increasing levels of ROS. Under low concentrations, ROS may function as signaling molecules favoring tumorigenesis and heterogeneity, while under high ROS concentrations, these species may work as cancer modulators due to their deleterious, genotoxic or even proapoptotic effect on cancer cells. This double-edged sword effect represented by ROS relies on their ability to cause genetic and epigenetic modifications in DNA structure. Antitumor therapeutic approaches may use molecules that prevent the ROS formation precluding carcinogenesis or use chemical agents that promote a sudden increase of ROS causing considerable oxidative stress inside tumor mass. Therefore, herein, we review what ROS are and how they are produced in normal and in cancer cells while providing an argumentative discussion about their role in cancer pathophysiology. We also describe the various sources of ROS in cancer and their role in tumor heterogeneity. Further, we also discuss some therapeutic strategies from the current landscape of cancer heterogeneity, ROS modulation, or ROS production.
Materials and Methods
ChemicalAmino-ethyl phosphoric ester was prepared according to [9] with purity over 99% analyzed by High-performance liquid chromatography (HPLC). The stock solution 1M was dissolved in water and stored at room temperature for in vitro and in vivo test.
Cell cultureB16F10 murine melanoma (CLR 6475) and human fibroblast (CCL-75) cell lines were obtained from the American Type Culture Collection (ATCC). B16F10 cells and fibroblasts were grown in RPMI-
BackgroundRenal cell carcinoma (RCC) is the most common type of kidney cancer, and represents the third most common urological malignancy. Despite the advent of targeted therapies for RCC and the improvement of the lifespan of patients, its cost-effectiveness restricted the therapeutic efficacy. In a recent report, we showed that synthetic phosphoethanolamine (Pho-s) has a broad antitumor activity on a variety of tumor cells and showed potent inhibitor effects on tumor progress in vivo.Methodology/Principal FindingsWe show that murine renal carcinoma (Renca) is more sensitive to Pho-s when compared to normal immortalized rat proximal tubule cells (IRPTC) and human umbilical vein endothelial cells (HUVEC). In vitro anti-angiogenic activity assays show that Pho-s inhibits endothelial cell proliferation, migration and tube formation. In addition, Pho-s has anti-proliferative effects on HUVEC by inducing a cell cycle arrest at the G2/M phase. It causes a decrease in cyclin D1 mRNA, VEGFR1 gene transcription and VEGFR1 receptor expression. Pho-s also induces nuclear fragmentation and affects the organization of the cytoskeleton through the disruption of actin filaments. Additionally, Pho-s induces apoptosis through the mitochondrial pathway. The putative therapeutic potential of Pho-s was validated in a renal carcinoma model, on which our remarkable in vivo results show that Pho-s potentially inhibits lung metastasis in nude mice, with a superior efficacy when compared to Sunitinib.Conclusions/SignificanceTaken together, our findings provide evidence that Pho-s is a compound that potently inhibits lung metastasis, suggesting that it is a promising novel candidate drug for future developments.
Background:We recently showed that synthetic phosphoethanolamine reduces tumour growth and inhibits lung metastasis in vivo. Here, we investigated its anti-leukaemia effects using acute promyelocytic leukaemia (APL) as a model.Methods:Cytotoxic effects of Pho-s on leukaemia cells were evaluated by MTT assay. Leukaemic cells obtained from hCG-PML-RARa transgenic mice were transplanted to NOD/SCID mice. After the animals were diagnosed as leukaemic, treatment started with Pho-s using all-trans retinoid acid or daunorubicin as positive control or and saline control. Cell morphology and immunophenotyping were used to detect the undifferentiated blast cells in the spleen, liver and bone marrow. The induction of apoptosis in vitro and in malignant leukaemic clones was evaluated.Results:Synthetic phosphoethanolamine is cytotoxic and induces apoptosis through the mitochondrial pathway in vitro to leukaemia cell lines. In vivo Pho-s exhibits anti-proliferative effects in APL model reducing the number of CD117+ and Gr-1+ immature myeloid cells in the BM, spleen and liver. Synthetic phosphoethanolamine impairs the expansion of malignant clones CD34+/CD117+, CD34+ and Gr-1+ in the BM. In addition, Pho-s induces apoptosis of immature cells in the spleen and liver, a notable effect.Conclusion:Synthetic phosphoethanolamine has anti-leukaemic effects in an APL model by inhibiting malignant clone expansion, suggesting that it is an interesting compound for leukaemia treatment.
Crotoxin (CTX) is the main neurotoxic component of Crotalus durissus terrificus snake venom. It inhibits tumour growth and modulates the function of macrophages, which are essential cells in the tumour microenvironment. The present study investigated the effect of CTX on the secretory activity of monocultured macrophages and macrophages co-cultivated with LLC-WRC 256 cells. The effect of the macrophage secretory activities on tumour cell proliferation was also evaluated. Macrophages pre-treated with CTX (0.3 μg/mL) for 2 h were co-cultivated with LLC-WRC 256 cells, and the secretory activity of the macrophages was determined after 12, 24 and 48 h. The co-cultivation of CTX-treated macrophages with the tumour cells caused a 20% reduction in tumour cell proliferation. The production of both H2O2 and NO was increased by 41% and 29% after 24 or 48 h of co-cultivation, respectively, compared to the values for the co-cultures of macrophages of control. The level of secreted IL-1β increased by 3.7- and 3.2-fold after 12 h and 24 h of co-cultivation, respectively. Moreover, an increased level of LXA4 (25%) was observed after 24 h of co-cultivation, and a 2.3- and 2.1-fold increased level of 15-epi-LXA4 was observed after 24 h and 48 h, respectively. Boc-2, a selective antagonist of formyl peptide receptors, blocked both the stimulatory effect of CTX on the macrophage secretory activity and the inhibitory effect of these cells on tumour cell proliferation. Taken together, these results indicate that CTX enhanced the secretory activity of macrophages, which may contribute to the antitumour activity of these cells, and that activation of formyl peptide receptors appears to play a major role in this effect.
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