Paradoxical action of PP2A inhibition and its potential for therapeutic sensitization.

The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.

In Vitro Evaluation of Ferutinin Rich-Ferula communis L., ssp. glauca, Root Extract on Doxorubicin-Induced Cardiotoxicity: Antioxidant Properties and Cell Cycle Modulation.

The clinical use of anthracycline Doxorubicin as an antineoplastic drug in cancer therapy is limited by cardiotoxic effects that can lead to congestive heart failure. Recent studies have shown several promising activities of different species of the genus Ferula belonging to the Apiaceae Family. Ferula communis is the main source of Ferutinin-a bioactive compound isolated from many species of Ferula-studied both in vitro and in vivo because of their different effects, such as estrogenic, antioxidant, anti-inflammatory, and also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. However, the potential protective role of Ferutinin in myocardium impairment, caused by chemotherapeutic drugs, still represents an unexplored field. The aim of this study was to test the effects of Ferutinin rich-Ferula communis L. root extract (FcFE) at different concentrations on H9C2 cells. Moreover, we evaluated its antioxidant properties in cardiomyocytes in order to explore new potential therapeutic activities never examined before in other experimental works. FcFE, at a concentration of 0.25 µM, in the H9C2 line, significantly reduced the ROS production induced by H2O2 (50 µM and 250 µM) and traced the cell mortality of the H9C2 co-treated with Ferutinin 0.25 µM and Doxorubicin (0.5 µM and 1 µM) to control levels. These results showed that FcFE could protect against Doxorubicin-induced cardiotoxicity. Further molecular characterization of this natural compound may open the way for testing FcFE at low concentrations in vivo and in clinical studies as an adjuvant in cancer therapy in association with anthracyclines to prevent side effects on heart cells.

Bacterial cyclomodulins: types and roles in carcinogenesis.

Various studies confirmed that bacterial infections contribute to carcinogenesis through the excessive accumulation of reactive oxygen species (ROS) and the expression of toxins that disrupt the cell cycle phases, cellular regulatory mechanisms and stimulate the production of tumorigenic inflammatory mediators. These toxins mimic carcinogens which act upon key cellular targets and result in mutations and genotoxicities. The cyclomodulins are bacterial toxins that incur cell cycle modulating effects rendering the expressing bacterial species of high carcinogenic potentiality. They are either cellular proliferating or cell cycle arrest cyclomodulins. Notably, cyclomodulins expressing bacterial species have been linked to different human carcinomas. For instance, Escherichia coli species producing the colibactin were highly prevalent among colorectal carcinoma patients, CagA+ Helicobacter pylori species were associated with MALT lymphomas and gastric carcinomas and Salmonella species producing CdtB were linked to hepatobiliary carcinomas. These species stimulated the overgrowth of pre-existing carcinomas and induced hyperplasia in in vivo animal models suggesting a role for the cyclomodulins in carcinogenesis. Wherefore, the prevalence and mode of action of these toxins were the focus of many researchers and studies. This review discusses different types of bacterial cyclomodulins highlighting their mode of action and possible role in carcinogenesis.

Targeting dormant tumor cells to prevent cancer recurrence.

Over the years, developments in oncology led to significantly improved clinical outcome for cancer patients. However, cancer recurrence after initial treatment response still poses a major challenge, as it often involves more aggressive, metastatic disease. The presence of dormant cancer cells is associated with recurrence, metastasis, and poor clinical outcome, suggesting that these cells may play a crucial role in the process of disease relapse. Cancer cell dormancy typically presents as growth arrest while retaining proliferative capacity and can be induced or reversed by a wide array of cell-intrinsic and cell-extrinsic factors. Conventional therapies preferentially target fast-dividing cells, leaving dormant cancer cells largely insensitive to these treatments. In this review, we discuss the role of dormant cancer cells in cancer recurrence and highlight how novel therapy strategies based on cell-cycle modulation, modifications of existing drugs, or enhanced drug-delivery vehicles may be used to specifically target this subpopulation of tumor cells, and thereby have the potential to prevent disease recurrence.

Comparative Phytochemical Characterization, Genetic Profile, and Antiproliferative Activity of Polyphenol-Rich Extracts from Pigmented Tubers of Different Solanum tuberosum Varieties.

Plants produce a vast array of biomolecules with beneficial effects for human health. In this study, polyphenol and anthocyanin-rich extracts (PAE) from pigmented tubers of Solanum tuberosum L. varieties "Blue Star", "Magenta Love", and "Double Fun" in comparison with the more extensively studied "Vitelotte" were evaluated and compared for antiproliferative effects in human leukemia cells, and their phytochemical and genetic profiles were determined. In U937 cells, upon treatment with PAE, it was possible to reveal the expression of specific apoptotic players, such as caspase 8, 9, 3, and poly (ADP-ribose) polymerase (PARP), as well as the induction of monocyte and granulocyte differentiation. A liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) investigation revealed the presence of polyphenolic compounds in all the varieties of potatoes analyzed, among which caffeoyl and feruloyl quinic acid derivatives were the most abundant, as well as several acylated anthocyanins. Each pigmented variety was genotyped by DNA-based molecular markers, and flavonoid-related transcription factors were profiled in tubers in order to better characterize these outstanding resources and contribute to their exploitation in breeding. Interesting biological activities were observed for "Blue Star" and "Vitelotte" varieties with respect to the minor or no effect of the "Double Fun" variety.

Impact of sodium butyrate and mild hypothermia on metabolic and physiological behaviour of CHO TF 70R cells

Background: To reduce costs associated with productivity of recombinant proteins in the biopharmaceutical industry, research has been focused on regulatory principals of growth and survival during the production phases of the cell culture. The main strategies involve the regulation of cell proliferation by the modulation of cell cycle control points (G1/S or G2/M) with mild hypothermia and the addition of sodium butyrate (NaBu). In this study, batch culture strategies were evaluated using CHO TF 70R cells producing the recombinant human tissue plasminogen activator (rh-tPA), to observe their individual and combined effect on the cellular physiological state and relevant kinetic parameters. Results: NaBu addition has a negative effect on the mitochondrial membrane potential (ΔΨm), the values of which are remarkably diminished in cultures exposed to this cytotoxic compound. This effect was not reflected in a loss of cell viability. NaBu and mild hypothermic conditions increased the doubling time in the cell cultures, suggesting that these strategies triggered a general slowing of each cell cycle phase in a different way. Finally, the individual and combined effect of NaBu and mild hypothermia produced an increase in the specific rh-tPA productivity in comparison to the control at 37°C without NaBu. Nevertheless, both strategies did not have a synergistic effect on the specific productivity. Conclusions: The combination of NaBu addition and mild hypothermic condition causes an impact on physiological and metabolic state of CHO TF 70R cells, decreasing cell growth rate and improving glucose consumption efficiency. These results therefore provide a promising strategy to increase specific productivity of rh-tPA.

Molecular mechanisms of cisplatin cytotoxicity in acute promyelocytic leukemia cells.

Cis-diamminedichloroplatinum (II) (cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in acute promyelocytic leukemia (APL) cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. We used the APL cell line as a model, and applied a variety of molecular tools to elucidate the cytotoxic mode of action of cisplatin. We found that cisplatin inhibited cell proliferation by a cytotoxicity, characterized by DNA damage and modulation of oxidative stress. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity. It also down regulated the p38MAPK pathway. Overall, this study highlights the molecular mechanisms that underline cisplatin toxicity to APL cells, and provides insights into selection of novel targets and/or design of therapeutic agents to treat APL.

Viral-mediated expression of c-Myc and cyclin A2 induces cochlear progenitor cell proliferation.

Cochlear progenitor cells have a limited proliferative capability, which prevents their application in treating sensorineural hearing loss. In this study, we showed that the expression of c-Myc and cyclin A2 was down-regulated during the development of cochlear tissue and CPC differentiation. Over-expression of these two genes using adenovirus transduction, significantly affected the CPC cell cycle and promoted the CPC proliferation. We further demonstrated that this promotion involves the classic CKI-cyclin-CDK pathway. Our study suggests that genetically modified CPCs may be a promising cell source for cochlear stem cell transplantation that improves the efficacy of cell therapy.