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Cigarette smoke has a crucial impact on transcriptome alteration by its effect on chromatin remodeling and DNA methylation status. The first mechanism is associated with the histone acetylation/deacetylation balance damage as a result of increased activity of NFĸB and lipid peroxidation products, which lead to an increased activity of HATs and DNMTs and reduced HDACs. The second mechanism is connected with direct damaging of DNA by smoke components, activation of downstream repair mechanism and recruitment of DNMTs into the breakage site, 'nicotine effect' and carbon monoxide (CO) activity on gene transcription and DNA methylation reduction. Cigarette smoking activates oxidative and inflammatory response and leads to uncontrolled structural changes in airways and alters gene expression. Such changes have a characteristic similar to that for COPD patients. Therefore, smoking is determined as a key risk factor for chronic respiratory disease development. Furthermore, electronic cigarettes, an alternative of tobacco cigarettes, also affect gene expression profile, which suggests some similarities in action mechanisms for both conventional and electronic cigarettes. However, there is only a limited number of trials discussing this issue and future investigations are needed.

DNA Double-strand breaks are considered one of the most lethal form of DNA damage. Many effective anticancer therapeutic approaches used chemical and physical methods to generate DNA double-strand breaks in the cancer cells. They include: IR and drugs which mimetic its action, topoisomerase poisons, some alkylating agents or drugs which affected DNA replication process. On the other hand, cancer cells are mostly characterized by highly effective systems of DNA damage repair. There are two main DNA repair pathways used to fix double-strand breaks: NHEJ and HRR. Their activity leads to a decreased effect of chemotherapy. Targeting directly or indirectly the DNA double-strand breaks response by inhibitors seems to be an exciting option for anticancer therapy and is a part of novel trends that arise after the clinical success of PARP inhibitors. These trends will provide great opportunities for the development of DNA repair inhibitors as new potential anticancer drugs. The main objective of this article is to address these new promising advances.

Topoisomerase II (Topo2) inhibitors in combination with cisplatin represent a common treatment modality used for glioma patients. The main mechanism of their action involves induction of DNA double-strand breaks (DSBs). DSBs are repaired via the homology-dependent DNA repair (HRR) and non-homologous end-joining (NHEJ). Inhibition of the NHEJ or HRR pathway sensitizes cancer cells to the treatment. In this work, we investigated the effect of three Topo2 inhibitors-etoposide, NK314, or HU-331 in combination with cisplatin in the U-87 human glioblastoma cell line. Etoposide as well as NK314 inhibited Topo2 activity by stabilizing Topo2-DNA cleavable complexes whereas HU-331 inhibited the ATPase activity of Topo2 using a noncompetitive mechanism. To increase the effectiveness of the treatment, we combined cisplatin and Topo2 inhibitor treatment with DSB repair inhibitors (DRIs). The cells were sensitized with NHEJ inhibitor, NU7441, or the novel HRR inhibitor, YU238259, prior to drug treatment. All of the investigated Topo2 inhibitors in combination with cisplatin efficiently killed the U-87 cells. The most cytotoxic effect was observed for the cisplatin + HU331 treatment scheme and this effect was significantly increased when a DRI pretreatment was used; however, we did not observed DSBs. Therefore, the molecular mechanism of cytotoxicity caused by the cisplatin + HU331 treatment scheme is yet to be evaluated. We observed a concentration-dependent change in DSB levels and accumulation at the G2/M checkpoint and S-phase in glioma cells incubated with NK314/cisplatin and etoposide/cisplatin. In conclusion, in combination with cisplatin, HU331 is the most potent Topo2 inhibitor of human glioblastoma cells.

Etoposide (VP-16) is the topoisomerase 2 (Top2) inhibitor used for treating of glioma patients however at high dose with serious side effects. It induces DNA double-strand breaks (DSBs). These DNA lesions are repaired by non-homologous DNA end joining (NHEJ) mediated by DNA-dependent protein kinase (DNA-PK). One possible approach to decrease the toxicity of etoposide is to reduce the dose while maintaining the anticancer potential. It could be achieved through combined therapy with other anticancer drugs. We have assumed that this objective can be obtained by (1) a parallel topo2 α inhibition and (2) sensitization of cancer cells to DSBs. In this work we investigated the effect of two Top2 inhibitors NK314 and VP-16 in glioma cell lines (MO59 K and MO59 J) sensitized by DNA-PK inhibitor, NU7441. Cytotoxic effect of VP-16, NK314 alone and in combination on human glioblastoma cell lines, was assessed by a colorimetric assay. Genotoxic effect of anticancer drugs in combination with NU7441 was assessed by comet assay. Cell cycle distribution and apoptosis were analysed by flow cytometry. Compared with VP-16 or NK314 alone, the combined treatment significantly inhibited cell proliferation. Combination treatment was associated with a strong accumulation of DSBs, modulated cell cycle phases distribution and apoptotic cell death. NU7441 potentiated these effects and additionally postponed DNA repair. Our findings suggest that NK314 could overcome resistance of MO59 cells to VP-16 and NU7441 could serve as sensitizer to VP-16/ NK314 combined treatment. The combined tripartite approach of chemotherapy could reduce the overall toxicity associated with each individual therapy, while concomitantly enhancing the anticancer effect to treat human glioma cells. Thus, the use of a tripartite combinatorial approach could be promising and more efficacious than mono therapy or dual therapy to treat and increase the survival of the glioblastoma patients.

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When e-cigarettes and, later on, heat-not-burn products were introduced to the market, it was hypothesized that they could have some positive effect on smoking cessation and reduction of smokers' exposure to dangerous substances. Despite some of their benefits, toxicological studies show the presence of some hazardous substances in their vapors, which may affect smokers' health in a similar way as tobacco cigarette compounds. There is a small amount of research studying the effects of these alternative cigarettes on health consequences in humans. In addition, the great majority of them compare only health effects of switching to e-cigarettes or heat-not-burn (HnB) products, without specifying their impact on non-smokers. Long-term exposure effects of e-cigarettes and heat-not-burn cigarettes and their effect on maternal health or fetus development are still unknown. Key woRds smoking, health consequence, tobacco cigarette, e-cigarette, heat-not-burn product. stReszczenie Wprowadzenie na rynek produktów alternatywnych do wyrobów tytoniowych, takich jak e-papierosy czy papierosy typu IQOS, z założenia powinno pozytywnie wpływać na zmniejszenie narażenia palaczy na niebezpieczne związki chemiczne zawarte w dymie tytoniowym lub wspierać rzucenie palenia. Pomimo sugerowanych korzyści przeprowadzone badania toksykologiczne wykazały obecność w wytwarzanych w nich oparach niebezpiecznych związków chemicznych. Wyniki te sugerują, że palenie e-papierosów lub papierosów typu IQOS w podobny sposób do konwencjonalnych wyrobów tytoniowych może niekorzystnie wpływać na zdrowie ich użytkowników. Niewiele jest jednak badań z udziałem ludzi dotyczących konsekwencji zdrowotnych stosowania tych wyrobów. Większość z nich porównuje skutki zdrowotne ich używania zamiast konwencjonalnych papierosów bez określenia wpływu na osoby wcześniej niepalące. Ponadto nie zostały dotychczas ustalone skutki zdrowotne długotrwałego palenia e-papierosów lub papierosów typu IQOS oraz ich wpływ na rozwój płodu lub zdrowie kobiet w ciąży. słowa Kluczowe palenie, konsekwencje zdrowotne, wyroby tytoniowe, e-papierosy, papierosy typu IQOS.