- DNA Fragile Site Breakage as a Measure of Chemical Exposure and Predictor of Individual Susceptibility to Form Oncogenic Rearrangements. [Journal Article]
- CCarcinogenesis 2017 Jan 09
- Chromosomal rearrangements induced by non-radiation causes contribute to the majority of oncogenic fusions found in cancer. Treatment of human thyroid cells with fragile site-inducing laboratory chem...
Chromosomal rearrangements induced by non-radiation causes contribute to the majority of oncogenic fusions found in cancer. Treatment of human thyroid cells with fragile site-inducing laboratory chemicals can cause preferential DNA breakage at the RET gene and generate the RET/PTC1 rearrangement, a common driver mutation in papillary thyroid carcinomas (PTC). Here, we demonstrate that treatment with non-cytotoxic levels of environmental chemicals (benzene and diethylnitrosamine) or chemotherapeutic agents (etoposide and doxorubicin) generates significant DNA breakage within RET at levels similar to those generated by fragile site-inducing laboratory chemicals. This suggests that chronic exposure to these chemicals plays a role in the formation of non-radiation associated RET/PTC rearrangements. We also investigated whether the sensitivity of the fragile RET region could predict the likelihood of rearrangement formation using normal thyroid tissues from patients with and without RET/PTC rearrangements. We found that normal cells of patients with thyroid cancer driven by RET/PTC rearrangements have significantly higher blunt-ended, double-stranded DNA breaks at RET than those of patients without RET/PTC rearrangements. This sensitivity of a cancer driver gene suggests for the first time that a DNA breakage test at the RET region could be utilized to evaluate susceptibility to RET/PTC formation. Further, the significant increase of blunt-ended, double-stranded DNA breaks, but not other types of DNA breaks, in normal cells from patients with RET/PTC-driven tumors suggests that blunt-ended double-stranded DNA breaks are a preferred substrate for rearrangement formation, and implicate involvement of the non-homologous end joining pathway in the formation of RET/PTC rearrangements.
- Sperm aneuploidy after testicular cancer treatment: data from a prospective multicenter study performed within the French Centre d'Étude et de Conservation des Oeufs et du Sperme network. [Journal Article]
- FSFertil Steril 2017 Jan 06
- CONCLUSIONS: Genetic counseling of TC patients should include information on the potential elevated risk of aneuploid conceptus from sperm recovered after treatment and the necessity to postpone conception up to ≥12 months after radiotherapy and ≥24 months after more than two BEP chemotherapy cycles. However, few men receiving one or two BEP cycles and some dropouts are the main limitations of this study.
- Nucleolar aggresomes mediate release of pericentric heterochromatin and nuclear destruction of genotoxically treated cancer cells. [Journal Article]
- NNucleus 2017 Jan 09; :0
- The role of the nucleolus and autophagy in maintenance of nuclear integrity is poorly understood. In addition, the mechanisms of nuclear destruction in cancer cells senesced after conventional chemot...
The role of the nucleolus and autophagy in maintenance of nuclear integrity is poorly understood. In addition, the mechanisms of nuclear destruction in cancer cells senesced after conventional chemotherapy are unclear. In an attempt to elucidate these issues, we studied teratocarcinoma PA1 cells treated with Etoposide (ETO), focussing on the nucleolus. Following treatment, most cells enter G2 arrest, display persistent DNA damage and activate p53, senescence, and macroautophagy markers. 2-5 µm sized nucleolar aggresomes (NoA) containing fibrillarin (FIB) and damaged rDNA, colocalised with ubiquitin, pAMPK, and LC3-II emerge, accompanied by heterochromatin fragments, when translocated perinuclearly. Microscopic counts following application of specific inhibitors revealed that formation of FIB-NoA is dependent on deficiency of the ubiquitin proteasome system coupled to functional autophagy. In contrast, the accompanying NoAs release of pericentric heterochromatin, which exceeds their frequency, is favoured by debilitation of autophagic flux. Potential survivors release NoA in the cytoplasm during rare mitoses, while exit of pericentric fragments often depleted of H3K9Me3, with or without encompassing by NoA, occurs through the nucleolar protrusions and defects of the nuclear envelope. Foci of LC3-II are accumulated in the nucleoli undergoing cessation of rDNA transcription. As an origin of heterochromatin fragmentation, the unscheduled DNA synthesis and circular DNAs were found in the perinucleolar heterochromatin shell, along with activation and retrotransposition of ALU elements, colocalised with 45S ribosomal DNA in NoAs. The data indicate coordination of the basic nucleolar function with autophagy regulation in maintenance of the integrity of the nucleolus associated domains secured by inactivity of retrotransposons.
- Dramatic Reduction in Tumor Size During 5 Months of Pazopanib Therapy in Combination With Ifosfamide, Carboplatin, and Etoposide in an Early Infant With Progressive Soft Tissue Sarcoma. [Journal Article]
- JPJ Pediatr Hematol Oncol 2017 Jan 06
- Primary Cutaneous T Cell Lymphoma (Gamma Delta subtype). [Journal Article]
- MJMed J Malaysia 2016; 71(5):296-297
- Primary cutaneous T-cell lymphoma gamma-delta subtype is an extremely rare entity of all the cutaneous T-cell lymphomas. Our case provides an insight on clinical behavior and treatment response with ...
Primary cutaneous T-cell lymphoma gamma-delta subtype is an extremely rare entity of all the cutaneous T-cell lymphomas. Our case provides an insight on clinical behavior and treatment response with feasible effective combination chemotherapy. We believe this will be of great interest to clinicians when facing this difficult clinical entity. We present a case of a 66-year-old Malay man with a threeweek history of rapidly growing skin nodules and plaques which spread throughout his body. He was commenced on combination chemotherapy gemcitabine, etoposide, and carboplatin with near complete remission on completion of second cycle but he defaulted. He relapsed within a month and he progressed despite treatment with the same regime. He was salvaged with fludarabine, cytarabine, and vinblastine combination chemotherapy but progressed with brain metastasis and died. However, more investigations and studies need to be done in this relatively unknown rare entity. A rare lymphoma registry might be of help to better understand and treat similar conditions.
- Novel indolizino[8,7-b]indole hybrids as anti-small cell lung cancer agents: Regioselective modulation of topoisomerase II inhibitory and DNA crosslinking activities. [Journal Article]
- EJEur J Med Chem 2016 Dec 24; 127:235-249
- A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of β-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antit...
A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of β-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antitumor evaluation. Of tumor cell lines tested, small cell lung cancer (SCLC) cell lines are the most sensitive to the newly synthesized compounds. These hybrids induce cell cycle arrest at the G2/M phase, trigger tumor cell apoptotic death, and display diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Intriguingly, the substituent at N(11) (H or Me) plays a critical role in modulating Topo II inhibition and DNA cross-linking activities. N(11)-Me derivatives predispose to induce DNA crosslinks, whereas N(11)-H derivatives potently inhibit Topo II. Computational analysis implicates that N(11)-Me restrict the torsion angles of the two adjacent OH on pyrrole resulting in a favorable of DNA cross-linking. Among these hybrids, compound 17a with N(11)-H is more effective than cisplatin and etoposide, but as potent as irinotecan, against the growth of SCLC H526 cells in xenograft model.
- Nephrotic Syndrome in Small Cell Lung Cancer and Induction of C-Mip in Podocytes. [Journal Article]
- AJAm J Kidney Dis 2017 Jan 04
- Paraneoplastic nephrotic syndrome is often a complication in patients with cancer, and various histologic lesions have been described in the kidney. We report the case of a 76-year-old woman who pres...
Paraneoplastic nephrotic syndrome is often a complication in patients with cancer, and various histologic lesions have been described in the kidney. We report the case of a 76-year-old woman who presented with a podocytopathy that was found to be associated with a small cell lung carcinoma (SCLC). One cycle of carboplatin-etoposide combination therapy led to resolution of nephrotic syndrome and remission of the lung carcinoma. C-Maf-inducing protein (C-Mip) was overexpressed in both podocytes and cancer cells, but was not found in control kidney and lung tissue samples. C-Mip also was absent in SCLC cells from 30 patients without nephrotic syndrome. Exposing cultured podocytes to a sample of our patient's serum that was collected prior to chemotherapy led to disorganization of the podocyte cytoskeleton and induction of C-Mip expression, which was not observed with control serum or our patient's serum sampled after chemotherapy. These observations suggest that C-Mip may play an important role in SCLC-related podocytopathy and that a circulating factor likely induces its expression in the kidney.
- Hesperetin-etoposide combinations induce cytotoxicity in U2OS cells: Implications on therapeutic developments for osteosarcoma. [Journal Article]
- DRDNA Repair (Amst) 2016 Dec 28
- Osteosarcoma chemotherapy has improved survival rates, however, chemoresistance and drug toxicity still limit therapy. Drug combinations may overcome these limitations by allowing fewer chemoresistan...
Osteosarcoma chemotherapy has improved survival rates, however, chemoresistance and drug toxicity still limit therapy. Drug combinations may overcome these limitations by allowing fewer chemoresistant cells to survive. The aim of this study was to evaluate the cytotoxic potential of hesperetin to osteosarcoma and to analyze the cell cycle effects of combinations of hesperetin with chemotherapeutic agents. For this, the U2OS human osteosarcoma cell line was exposed to hesperetin or hesperetin combined with etoposide or doxorubicin in defined proportions. Hesperetin was less cytotoxic compared to chemotherapeutic agents, as shown by cell growth, viability and clonogenic assays. Notwithstanding, hesperetin combined with etoposide showed additive effects on the inhibition of cell growth. Furthermore, hesperetin induced G2-phase arrest, associated with decreased gene expression of cyclins B1 and E1 and cyclin-dependent kinases 1 and 2. The combination with higher additive effect resulted in higher percentage of cells in G2-phase, showing that G2-phase arrest is associated with cytotoxicity. Moreover, hesperetin induced cytostatic effects. In conclusion, our results suggest that G2-phase arrest is an important step for hesperetin-induced cytotoxicity in U2OS cells. Hesperetin shows potential cytotoxicity when combined with etoposide, which may have implications on therapeutic developments for osteosarcoma.
- ViscumTT induces apoptosis and alters IAP expression in osteosarcoma in vitro and has synergistic action when combined with different chemotherapeutic drugs. [Journal Article]
- BCBMC Complement Altern Med 2017 Jan 07; 17(1):26
- CONCLUSIONS: ViscumTT treatment results in synergistic apoptosis induction in osteosarcoma cells in vitro and ex vivo. Additionally, conventional standard chemotherapeutic drugs such as doxorubicin, etoposide and ifosfamide were able to dramatically enhance apoptosis induction. These results promise a high potential of viscumTT as an additional adjuvant therapy approach for osteosarcoma.
Previous New Search Next
- L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. [Journal Article]
- OOncotarget 2017 Jan 04
- Retinoblastoma is the most common intraocular cancer in children, affecting 1/20,000 live births. Currently, children with retinoblastoma were treated with chemotherapy using drugs such as carboplati...
Retinoblastoma is the most common intraocular cancer in children, affecting 1/20,000 live births. Currently, children with retinoblastoma were treated with chemotherapy using drugs such as carboplatin, vincristine, and etoposide. Unfortunately, if conventional treatment fails, the affected eyes should be removed to prevent extension into adjacent tissues and metastasis. This study is to investigate the roles of L1 in adhesion-mediated proliferation and chemoresistance of retinoblastoma. L1 was differentially expressed in 30 retinoblastoma tissues and 2 retinoblastoma cell lines. Furthermore, the proportions of L1-positive cells in retinoblastoma tumors were negatively linked with the number of Flexner-Wintersteiner rosettes, a characteristic of differentiated retinoblastoma tumors, in each tumor sample. Following in vitro experiments using L1-deleted and -overexpressing cells showed that L1 increased adhesion-mediated proliferation of retinoblastoma cells via regulation of cell cycle-associated proteins with modulation of Akt, extracellular signal-regulated kinase, and p38 pathways. In addition, L1 increased resistance against carboplatin, vincristine, and esoposide through up-regulation of apoptosis- and multidrug resistance-related genes. In vivo tumor formation and chemoresistance were also positively linked with the levels of L1 in an orthotopic transplantation model in mice. In this manner, L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. Targeted therapy to L1 might be effective in the treatment of retinoblastoma tumors, especially which rapidly proliferate and demonstrate resistance to conventional chemotherapeutic drugs.