Exploring the ATR-CHK1 pathway in the response of doxorubicin-induced DNA damages in acute lymphoblastic leukemia cells.

Doxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B-/T cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair, and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B-/T cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mitotic cells, including those showing tripolar spindles, metaphases with lagging chromosomes, and massive chromosomes fragmentation. In conclusion, we found that the ATR-CHK1 pathway is involved in the response to Dox-induced DNA damages and we demonstrated that our new in vitro drug schedule that combines Dox followed by ATR/CHK1 inhibitors can increase Dox cytotoxicity against ALL cells, while using lower drug doses. • Doxorubicin activates the G2/M cell cycle checkpoint in acute lymphoblastic leukemia (ALL) cells. • ALL cells respond to doxorubicin-induced DNA damages by activating the ATR-CHK1 pathway. • The inhibition of the ATR-CHK1 pathway synergizes with doxorubicin in the induction of cytotoxicity in ALL cells. • The inhibition of ATR-CHK1 pathway induces aberrant chromosome segregation and mitotic spindle defects in doxorubicin-pretreated ALL cells.

circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer.

Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.

Erratum to "Development of a New Sequential Extraction Procedure of Nickel Species on Workplace Airborne Particulate Matter: Assessing the Occupational Exposure to Carcinogenic Metal Species".

[This corrects the article DOI: 10.1155/2018/3812795.].

Biological monitoring of exposure to polycyclic aromatic hydrocarbons and to metallic elements in Italian Navy workers operating near the industrial area in Taranto (South Italy).

OBJECTIVES: To assess, by means of biological monitoring, exposure to polycyclic aromatic hydrocarbons (PAHs) and to metallic elements in Italian Navy workers operating near the industrial area in Taranto, and thereby estimate the health risk. METHODS: A total of 450 workers in the Italian Navy were examined; they had office type jobs, and 150 of them worked near the industrial area in Taranto (exposed group), 150 in Taranto but far from this area (internal control group) and 150 in Brindisi (external control group). The recruited workers were administered a questionnaire inquiring about current and previous working activities, personal medical history, lifestyle and dietary habits, and their residence location. Then they collected a urine sample for the determination of 1-hydroxypyrene, 2-naphthol, cotinine and the metallic elements As, Cd, Co, Cr, Mn, Ni, Pb, Cu, Zn and Hg. The latter were measured in 110 workers in each group. In addition, in some of the work sites of the three groups, environmental samplings were carried out to determine PAHs and the 10 metallic elements, also taking into account the wind direction. RESULTS: Airborne benzo(a)pyrene concentrations at the different sampling sites ranged from 0.02 to 0.06 ng/m3 and naphthalene between <25 and 65.3 ng/m3, regardless of the wind direction. Among the metallic elements, As, Cd, Co, Cr, Hg, Pb, Cu and Zn were present at concentrations below or just above the limit of detection (LOD). Mn and Ni were slightly higher in the work sites of the exposed group. The urinary concentrations of 1-hydroxypyrene, 2-naphthol and the single metallic elements were not higher in the exposed workers group than in the other 2 groups. Smokers had significantly higher urinary 1-hydroxypyrene and 2-naphthol concentrations, whereas cigarette smoking did not condition a higher urinary elimination of metallic elements in the three groups with the exception of Cd and Pb. Moreover, residence location conditioned Mn, Hg and As urinary excretion, consumption of shellfish and/or crustaceans in the 72 hours before urine collection conditioned As elimination, and consumption of legumes in the 72 hours before urine collection conditioned Ni elimination. CONCLUSIONS: This research did not find a higher urinary excretion of 1-hydroxypyrene, 2-naphthol and As, Cd, Co, Cr, Mn, Ni, Pb, Cu, Zn and Hg in the exposed workers group as compared to the internal control group working far from the industrial area of Taranto, nor in the group working in another city far away from Taranto, Brindisi. Therefore, it indicated that workers in the Italian Navy operating near the industrial area in Taranto were not exposed to a greater risk attributable to exposure to PAHs and metallic elements than the two control groups.