It is generally accepted that recent advances in anticancer agents have contributed significantly to the improvement of both the disease-free survival and quality of life in cancer patients. However, ...in many instances, a favorable initial response to treatment changes afterwards, thereby leading to cancer relapse and recurrence. This phenomenon of acquired resistance to therapy, it is a major problem for totally efficient anticancer therapy. The failure to obtain an initial response reflects a form of intrinsic resistance. Specific cell membrane transporter proteins are implicated in intrinsic drug resistance by altering drug transport and pumping drugs out of the tumor cells. Moreover, the gradual acquisition of specific genetic and epigenetic abnormalities in cancer cells could contribute greatly to acquired drug resistance. A critical issue in the clinical setting, is that the problem of drug resistance appears to have a negative effect on also the new molecularly-targeted anticancer drugs. Several ongoing efforts are being made by the medical community aimed to the identification of such resistance mechanisms and the development of novel drugs that could overcome them. In this review, the major drug resistance mechanisms and strategies to overcome them are critically discussed, and also possible future directions are suggested.
Radiation can cause as well as cure cancer. The risk of developing radiation-induced cancer has traditionally been estimated from cancer incidence among survivors of the atomic bombs in Hiroshima and ...Nagasaki1) These data provide the best estimate of human cancer risk over the dose range for low linear energy transfer (LET) radiations, such as X or γ-rays. The situation of estimating the real biological effects becomes even more difficult in the case of high LET particles encountered in space or as the result of domestic exposure to a-particles from radon gas emitters or other radioactive emitters like uranium-238. Complex DNA damage, i.e., the signature of high-LET radiations comprises of closely spaced DNA lesions forming a cluster of DNA damage. The two basic groups of complex DNA damage are double strand breaks (DSBs) and non-DSB oxidative clustered DNA lesions (OCDL). Theoretical analysis and experimental evidence suggest an increased complexity and severity of complex DNA damage with increasing LET (linear energy transfer) and a high mutagenic or carcinogenic potential. Data available on the formation of clustered DNA damage (DSBs and OCDL) by high-LET radiations are often controversial suggesting a variable response to dose and type of radiation. The chemical nature and cellular repair mechanisms of complex DNA damage have been much less characterized than those of isolated DNA lesions like an oxidized base or a single strand break especially in the case of high-LET radiation. This review will focus on the induction of clustered DNA damage by high-LET radiations presenting the earlier and recent relative data.
p21: A Two-Faced Genome Guardian Georgakilas, Alexandros G; Martin, Olga A; Bonner, William M
Trends in molecular medicine,
04/2017, Letnik:
23, Številka:
4
Journal Article
Recenzirano
Upon DNA damage or other stressors, the tumor suppressor p53 is activated, leading to transient expression of the cyclin-dependent kinase inhibitor (CKI) p21. This either triggers momentary G1 cell ...cycle arrest or leads to a chronic state of senescence or apoptosis, a form of genome guardianship. In the clinic, the presence of p21 has been considered an indicator of wildtype p53 activity. However, recent evidence suggests that p21 also acts as an oncogenic factor in a p53-deficient environment. Here, we discuss the controversial aspects of the two-faced involvement of p21 in cancer and speculate on how this new information may increase our understanding of its role in cancer pathogenesis. Prevailing notions indicate that p21 might also act as antiapoptotic agent, which may have relevant implications for future therapeutic strategies.
Breast cancer is a heterogeneous disease affecting thousands of people every year. Multiple factors are responsible in causing breast cancer while a number of treatment options are also available for ...the disease. Tamoxifen is the most widely used anti-estrogen for the treatment of hormone-dependent breast cancer. The specific drug is used as a hormonal therapy for patients who exhibit estrogen receptor positive breast cancer. The pharmacological activity of Tamoxifen is dependent on its conversion to its active metabolite, endoxifen, by CYP2D6. Tamoxifen reduces the risk of recurrence and death from breast cancer when given as adjuvant therapy and provides effective palliation for patients with metastatic breast cancer. In this review we focus on the role of Tamoxifen in breast cancer treatment including mechanisms and side-effects. Finally, we discuss in detail the exciting prospects that lie ahead.
The accumulated evidence in the literature indicates that a cluster of two or more lesions within one or two helical turns of the DNA is more challenging to repair than individual, widely dispersed ...lesions. The biological importance of clustered DNA lesions, especially complex double-strand breaks (DSB) and some types of non-DSB clusters (e.g., opposed bases that are oxidized), are now well known within the radiation research community. Still, many details of the induction and biological processing of complex clusters remain to be elucidated, especially in human cells. In this mini-review, we discuss recent advances in our understanding of the pathway(s) used by the mammalian cells to process and efficiently repair complex clusters other than the DSB. The effects of radiation quality and hypoxia on cluster induction and complexity are also briefly reviewed and discussed. Additional research is needed to better understand and quantify the multi-scale physiochemical and biological processes ultimately responsible for radiation-induced mutagenesis and genomic instability. New information and models to better quantify intermediate events (outcomes) related to the biological processing of non-DSB clusters are also important for ongoing efforts to assess the human health risks of terrestrial and space radiation environments and to guide the radiation therapy treatment planning process, especially for protons and carbon ions.
•Immune alterations are present in many ionizing radiation-induced adverse health outcomes.•Low doses of ionizing radiation induce subtle but persistent immune function alterations.•High doses are ...mainly immune suppressive, low dose effects are immune modulatory.•High doses are pro-inflammatory, low doses can have anti-inflammatory effects, as well.•Immune aging is accelerated by ionizing radiation.
Ionizing radiation interacts with the immune system in many ways with a multiplicity that mirrors the complexity of the immune system itself: namely the need to maintain a delicate balance between different compartments, cells and soluble factors that work collectively to protect, maintain, and restore tissue function in the face of severe challenges including radiation damage. The cytotoxic effects of high dose radiation are less relevant after low dose exposure, where subtle quantitative and functional effects predominate that may go unnoticed until late after exposure or after a second challenge reveals or exacerbates the effects. For example, low doses may permanently alter immune fitness and therefore accelerate immune senescence and pave the way for a wide spectrum of possible pathophysiological events, including early-onset of age-related degenerative disorders and cancer. By contrast, the so called low dose radiation therapy displays beneficial, anti-inflammatory and pain relieving properties in chronic inflammatory and degenerative diseases. In this review, epidemiological, clinical and experimental data regarding the effects of low-dose radiation on the homeostasis and functional integrity of immune cells will be discussed, as will be the role of immune-mediated mechanisms in the systemic manifestation of localized exposures such as inflammatory reactions. The central conclusion is that ionizing radiation fundamentally and durably reshapes the immune system. Further, the importance of discovery of immunological pathways for modifying radiation resilience amongst other research directions in this field is implied.
Cellular effects of ionizing radiation (IR) are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the ...nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs), single strand breaks (SSBs) and base lesions within a short DNA region of up to 15-20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1) repair resistant, increasing genomic instability (GI) and malignant transformation and (2) can be considered as persistent "danger" signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity). Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.
•Ionizing radiation causes adverse circulatory and metabolic effects at high doses.•Low-dose radiation is causally associated with circulatory disease.•Impact of low-dose radiation is modulated by ...inflammatory, stress, and immune responses.
Risks to health are the prime consideration in all human situations of ionizing radiation exposure and therefore of relevance to radiation protection in all occupational, medical, and public exposure situations. Over the past few decades, advances in therapeutic strategies have led to significant improvements in cancer survival rates. However, a wide range of long-term complications have been reported in cancer survivors, in particular circulatory diseases and their major risk factors, metabolic diseases. However, at lower levels of exposure, the evidence is less clear. Under real-life exposure scenarios, including radiotherapy, radiation effects in the whole organism will be determined mainly by the response of normal tissues receiving relatively low doses, and will be mediated and moderated by systemic effects. Therefore, there is an urgent need for further research on the impact of low-dose radiation. In this article, we review radiation-associated risks of circulatory and metabolic diseases in clinical, occupational or environmental exposure situations, addressing epidemiological, biological, risk modelling, and systems biology aspects, highlight the gaps in knowledge and discuss future directions to address these gaps.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first occurred in Wuhan (China) in December of 2019, causes a severe acute respiratory illness with a high mortality rate, and has ...spread around the world. To gain an understanding of the evolution of the newly emerging SARS-CoV-2, we herein analyzed the codon usage pattern of SARS-CoV-2. For this purpose, we compared the codon usage of SARS-CoV-2 with that of other viruses belonging to the subfamily of
. We found that SARS-CoV-2 has a high AU content that strongly influences its codon usage, which appears to be better adapted to the human host. We also studied the evolutionary pressures that influence the codon usage of five conserved coronavirus genes encoding the viral replicase, spike, envelope, membrane and nucleocapsid proteins. We found different patterns of both mutational bias and natural selection that affect the codon usage of these genes. Moreover, we show here that the two integral membrane proteins (matrix and envelope) tend to evolve slowly by accumulating nucleotide mutations on their corresponding genes. Conversely, genes encoding nucleocapsid (N), viral replicase and spike proteins (S), although they are regarded as are important targets for the development of vaccines and antiviral drugs, tend to evolve faster in comparison to the two genes mentioned above. Overall, our results suggest that the higher divergence observed for the latter three genes could represent a significant barrier in the development of antiviral therapeutics against SARS-CoV-2.
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