Krebswissenschaft und -therapie

The master regulators, cyclin dependant kinases (CDKs), are the actual driving forces behind the progression of cell cycle in eukaryotic cells. The activity level of these kinases is maintained and controlled by the periodic synthesis and degradation of positive regulators, cyclins, negative regulators, cyclin kinase inhibitors (CKIs) and other reversible phosphorylation events. CDK/cyclin complexes regulate each phase of the cell cycle and the breakdown of this regulation in any phase results in uncontrolled growth and thus tumor formation. If not all, most of the cancers show direct or indirect deregulation of these kinases, therefore targeting CDKs is an important mode to develop new anticancer therapeutics. Promising preclinical data of many compounds led to the entry of a few of these compounds into clinical trials where excellent results have maintained the high hopes and the recent discovery of one of these compounds as a commercially available drug has further enriched this area of research. So far much has been said about these essential targets but there is a need to discuss their role, mechanism, avenues and progress timely for further understanding of CDKs as anticancer drug targets and to learn how best new CDK inhibitors could be put into clinically developed agents.

Multidrug resistance is one of the most common causes of relapse in cancer chemotherapy. Inhibition of ABC transporters to reverse MDR is a prominent approach to enhance the efficacy of cancer chemotherapy. We investigated the effect of resveratrol (RSV) on the membrane transport function and the expression of proteins involved in the multidrug resistance in NCI-H460 cells. The molecular interactions of RSV with P-gp were analyzed by Schrodinger software. The membrane transport function and cell cycle distribution were measured using flow cytometry. The mRNA expression level of MDR1, LRP, MRP2, ABCC1, ABCC2 and ABCC3 genes were detected by qRT-PCR and BCRP expression was detected by western blot analysis. In silico docking studies revealed that RSV possesses greater binding affinity with TMD region of P-gp. In this study, RSV pretreatment significantly enhanced Paclitaxel (PTX) antiproliferative effect in NCI-H460 cells. The rhodamine 123 drug efflux studies revealed that there was a significant transport function inhibition by RSV treatment and moderate transport function inhibition by PTX. Further, RSV treatment significantly decreased the mRNA expression levels of various ABC transporters genes. Furthermore, expression of BCRP was found to be down-regulated during RSV treatment. It was also found that this enhanced anticancer efficacy of RSV was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Interestingly, we observed significantly enhanced antiproliferative effect, transport function inhibition and downregulation of ABC transporters in RSV-PTX combination group. This might be due to additive or synergistic effect of RSV with PTX in NCI-H460 cells. Thus, the present findings illustrate the modulatory role of RSV on PTX sensitization in relatively resistant NCI-H460 cells.

Psammaplin A is a phenolic marine metabolite that exhibits antitumor properties. There is evidence that Psammaplin A is a DNA methyltransferase (DNMT) inhibitor that sensitizes human cancer cells by suppressing DNA repair activity. There is also evidence that the drug is a histone deacetylase. The aim of this experiment is to test the efficacy of Psammaplin A as an anticancer therapeutic agent by comparing its effect on lung cancer cells NCI-H226 Bap1 null cells and on human neuroblastomal SKN cells. In the experiment SKN cells are used because they are more sensitive than normal cells, and toxicity can be discerned better with the use of SKN cells. Results show that at a concentration between 1/10 000 μL and 1/1000 μL of Psammaplin A significantly inhibits cell growth of the Bap1 null cells while presenting minimal toxicity to SKN cells. The results were particularly strong when CPT (a DNA-damage inducing drug) was added to the cells. This indicates that Psammaplin A is a potential adjuvant for cancer patients, particularly for Bap-1 null lung cancer patients being treated with DNA-damage inducing therapies. Results also confirm that Psammaplin A does not affect neuroblastoma or neuroblastomal pathways. Results also indicate, since Psammaplin A inhibition differs from MG132 inhibition of cell proliferation, that Psammaplin A does not inhibit proteasomes.

Substantial data from cell culture and animal studies evidence the preventive effect of statins, cholesterol lowering-drugs, in regulation of cancer cell proliferation and metastasis. Various clinical studies also support this correlation between use of statin and the reduction of cancer incidence. However, in some cases, statins have failed to decrease the risk of cancer. Since, instead of serum cholesterol, intracellular cholesterol may play a crucial role in the regulation of tumorigenesis and metastasis. The mechanism by which cholesterol is stored within cancer cells may differ among cancer types and also in different individuals. This paper discusses the molecular detail to speculate the statin-sensitive cancer. It also highlights that statins may work better as anticancer therapy if it is used with the combination of a specific microRNA (miR).

Introduction: Even though establishing good pain control is an important priority for patients with cancer, there are barriers for under treatment including poor attitudes towards pain and opioid analgesia and barriers which exist within the professionals. So, this assessment is conducted to assess the attitude, practice of nurses’ and barriers regarding cancer pain management at selected health institutions offering cancer treatment in Addis Ababa city, Ethiopia, 2013.

Methods: Cross-sectional study design was conducted. Anonymously structured self-administered questionnaire and focus group discussion was carried out among 82 nurses. Nurses’ Knowledge and Attitudes Survey Regarding Pain (NKARSP) questionnaire was used for data collection. Epi info version 3.5.4 and SPSS version 20 statistical software’s were used for data entry and analysis. to identify factors associated with attitude towards cancer pain management bivariate and multivariate logistics regression was computed. P-value and 95% confidence interval was used to determine the association.

Results: 45(54.9%) of the study participants were from the governmental hospital and the rest 37(45.1%) respondents were from private heath institutions. More than half, 53.7%, of the nurses’ have a negative attitude, towards cancer pain management. Similarly 65.9% of nurses’ had poor cancer pain management practice. Lack of courses related to pain in the under graduate classes, lack of continuing training, patient and work overload, role confusion, lack of motivation including salary were the identified barriers for adequate pain management. Monthly income of greater than 1500 Ethiopian Birr (ETB) were found to be associated with attitude towards cancer pain management (AOR=0.16, 95% CI=0.03-0.78).

Conclusion: Negative attitude of nurses regarding cancer pain management were observed. The practice of nurses’ was also poor. The main barriers which hinder good cancer pain management were lack of motivation including salary, role confusion, and lack of continuing training. An effort to improve educational development of nurses’ like in service trainings on cancer pain management and familiarization with WHO guidelines should be given to nurses who are working in cancer units.