Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein

The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy

In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies

The development of a drug-resistant cell line can take from 3 to 18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval, and optimizing the dose of drug for the parent cell line. Clinically relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between two- and eight-fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299 and H460) and temozolomide-resistant melanoma (Malme-3M and HT144) cell lines. Continuous selection produced a lapatinib-resistant breast cancer cell line (HCC1954). Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy, or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical drug resistance

Osteosarcopenia:Where Osteoporosis and Sarcopenia Collide

peer reviewedThe coexistence of osteoporosis and sarcopenia has been recently considered in some groups as a syndrome termed 'osteosarcopenia'. Osteoporosis describes low bone mass and deterioration of the micro-architecture of the bone, whereas sarcopenia is the loss of muscle mass, strength and function. With an ageing population the prevalence of both conditions is likely to increase substantially over the coming decades and is associated with significant personal and societal burden. The sequelae for an individual suffering from both conditions together include a greater risk of falls, fractures, institutionalization and mortality. The aetiology of 'osteosarcopenia' is multifactorial with several factors linking muscle and bone function, including genetics, age, inflammation and obesity. Several biochemical pathways have been identified that are facilitating the development of several promising therapeutic agents, which target both muscle and bone. In the current review we outline the epidemiology, pathogenesis and clinical consequences of 'osteosarcopenia' and explore current and potential future management strategies

Body mass index, prudent diet score and social class across three generations: evidence from the Hertfordshire Intergenerational Study.

BACKGROUND: Studies describing body mass index (BMI) and prudent diet score have reported that they are associated between parents and children. The Hertfordshire Intergenerational Study, which contains BMI, diet and social class information across three generations, provides an opportunity to consider the influence of grandparental and parental BMI and prudent diet score across multiple generations, and the influence of grandparental and parental social class on child BMI. METHODS: Linear regressions examining the tracking of adult BMI and prudent diet score across three generations (grandparent (F0), parent (F1) and child (F2)) were run from parent to child and from grandparent to grandchild. Linear mixed models investigated the influence of F0 and F1 BMI or prudent diet score on F2 BMI and prudent diet score. Linear regressions were run to determine whether social class and prudent diet score of parents and grandparents influenced the BMI of children and grandchildren. RESULTS: BMI was significantly associated across each generational pair and from F0 to F1 in multilevel models. Prudent diet score was significantly positively associated between grandparents and grandchildren. Lower grandparental and parental social class had a significantly positive association with F2 BMI (F0 low social class: b=1.188 kg/m2, 95% CI 0.060 to 2.315, p=0.039; F1 middle social class: b=2.477 kg/m2, 95% CI 0.726 to 4.227, p=0.006). CONCLUSION: Adult BMI tracks across generations of the Hertfordshire Intergenerational Study, and child BMI is associated with parental and grandparental social class. The results presented here add to literature supporting behavioural and social factors in the transmission of BMI across generations

Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells

Circulating miRNAs miR-34a and miR-150 associated with colorectal cancer progression

BACKGROUND: Screening for the early detection of colorectal cancer is important to improve patient survival. The aim of this study was to investigate the potential of circulating cell-free miRNAs as biomarkers of CRC, and their efficiency at delineating patients with polyps and benign adenomas from normal and cancer patient groups. METHODS: The expression of 667 miRNAs was assessed in a discovery set of 48 plasma samples comprising normal, polyp, adenoma, and early and advanced cancer samples. Three miRNAs (miR-34a, miR-150, and miR-923) were further examined in a validation cohort of 97 subjects divided into the same five groups, and in an independent public dataset of 40 CRC samples and paired normal tissues. RESULTS: High levels of circulating miR-34a and low miR-150 levels distinguished groups of patients with polyps from those with advanced cancer (AUC = 0.904), and low circulating miR-150 levels separated patients with adenomas from those with advanced cancer (AUC = 0.875). In addition, the altered expression of miR-34a and miR-150 in an independent public dataset of forty CRC samples and paired normal tissues was confirmed. CONCLUSION: We identified two circulating miRNAs capable of distinguishing patient groups with different diseases of the colon from each other, and patients with advanced cancer from benign disease groups. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1327-5) contains supplementary material, which is available to authorized users