Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.
Despite recent therapeutic advances, the prognosis of patients afflicted by glioblastoma remains poor, with a progression-free survival in the range of months, even with multimodal therapy including surgery, radio-and chemotherapy. Temozolomide (TMZ), an oral alkylating agent, has demonstrated activity against recurrent and newly diagnosed glioblastoma (Yung et al. 2000;Stupp et al. 2005), and is being used as the standard of care for newly diagnosed glioblastoma since 2005.The DNA repair protein O 6 -methylguanine methyltransferase (MGMT) removes O 6 -alkyl-guanine adducts from DNA through irreversible binding and degradation, thereby minimizing the DNA-damaging effects of alkylating agent chemotherapy (Wang et al. 1996;Phillips et al. 1997 Abstract Temozolomide (TMZ) is an alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma. Clinical benefit is more prominent in patients with methylation of the O 6 -methyl-guanine DNA methyltransferase (MGMT) promoter. However, all patients eventually suffer from tumor progression because their tumors become resistant to TMZ. Here, we modeled acquired TMZ resistance in glioma cells in vitro to identify underlying molecular mechanisms. To this end, the glioma cell lines LNT-229, LN-308, and LN-18 were exposed repetitively to increasing concentrations of TMZ to induce a stable resistant phenotype (R) defined by clonogenic survival assays. The molecular mechanisms mediating acquired resistance were assessed by immunoblot, PCR, and flow cytometry. Rescue experiments were performed with siRNA-mediated candidate gene silencing. We found in LN-18 cells constitutively expressing MGMT a strong up-regulation of MGMT levels in TMZ-resistant cells. TMZ resistance in the MGMT-negative cell lines LNT-229 and LN-308 was not associated with de novo expression of MGMT. Instead, we found a down-regulation of several DNA mismatchrepair proteins in resistant LNT-229 cells. A TMZ-resistant phenotype was also achieved by silencing selected DNA mismatch repair proteins in parental LNT-229 cells. No obvious mechanism of resistance was identified in the third cell line, LN-308, except for reduced methylation of LINE-1 repetitive elements. In conclusion, we demonstrate that different molecular mechanisms may contribute to the development of acquired TMZ resistance in glioma cells, indicating the need to develop distinct strategies to overcome resistance.
Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.
Metals and metal compounds are constituents of our natural environment. Their distribution depends on the existence of natural sources (e.g. volcanoes or erosion) and their use in human's activity. They are transformed naturally (e.g. by bacterial activity) with formation of organic species that influence their mobility and accumulation in abiotic as well as biotic systems. Up to date metal species are released into the environment questioning their influence on human health. Due to their widespread use in human activities such as industry, agriculture and even as medicine (e.g. As, Se, Pt), numerous health risks may be associated with exposure to these substances. Different reports on metal intoxication are documented and studies especially on neurotoxicity, genotoxicity, or carcinogenicity, are previously published in numerous articles. This mini-review gives an overview on the use and the actions of selected metal species of actual scientific concern, with a focus on neuronal cells.
The biochemical modification of the metals and metalloids mercury, tin, arsenic, antimony, bismuth, selenium, and tellurium via formation of volatile metal hydrides and alkylated species (volatile and involatile) performs a fundamental role in determining the environmental processing of these elements. In most instances, the formation of such species increases the environmental mobility of the element, and can result in bioaccumulation in lipophilic environments. While inorganic forms of most of these compounds are well characterized (e.g., arsenic, mercury) and some of them exhibit low toxicity (e.g., tin, bismuth), the more lipid-soluble organometals can be highly toxic. Methylmercury poisoning (e.g., Minamata disease) and tumor development in rats after exposure to dimethylarsinic acid or tributyltin oxide are just some examples. Data on the genotoxicity (and the neurotoxicity) as well as the mechanisms of cellular action of organometal(loid) compounds are, however, scarce. Many studies have shown that the production of such organometal(loid) species is possible and likely whenever anaerobic conditions (at least on a microscale) are combined with available metal(loid)s and methyl donors in the presence of suitable organisms. Such anaerobic conditions can exist within natural environments (e.g., wetlands, pond sediments) as well as within anthropogenic environmental systems (e.g., waste disposal sites and sewage treatments plants). Some methylation can also take place under aerobic conditions. This article gives an overview about the environmental distribution of organometal(loid) compounds and the potential hazardous effects on animal and human health. Genotoxic effects in vivo and in vitro in particular are discussed.
We analyzed an ex vivo model of in situ aged human dermal fibroblasts, obtained from 15 adult healthy donors from three different age groups using an unbiased quantitative proteome-wide approach applying label-free mass spectrometry. Thereby, we identified 2409 proteins, including 43 proteins with an age-associated abundance change. Most of the differentially abundant proteins have not been described in the context of fibroblasts’ aging before, but the deduced biological processes confirmed known hallmarks of aging and led to a consistent picture of eight biological categories involved in fibroblast aging, namely proteostasis, cell cycle and proliferation, development and differentiation, cell death, cell organization and cytoskeleton, response to stress, cell communication and signal transduction, as well as RNA metabolism and translation. The exhaustive analysis of protein and mRNA data revealed that 77% of the age-associated proteins were not linked to expression changes of the corresponding transcripts. This is in line with an associated miRNA study and led us to the conclusion that most of the age-associated alterations detected at the proteome level are likely caused post-transcriptionally rather than by differential gene expression. In summary, our findings led to the characterization of novel proteins potentially associated with fibroblast aging and revealed that primary cultures of in situ aged fibroblasts are characterized by moderate age-related proteomic changes comprising the multifactorial process of aging.
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