Doxorubicin-conjugated dexamethasone induced MCF-7 apoptosis without entering the nucleus and able to overcome MDR-1-induced resistance

Kamontip Chaikomon,1,2 Supreecha Chattong,1,3 Theerasak Chaiya,1 Danai Tiwawech,4 Yongsak Sritana-Anant,5 Amornpun Sereemaspun,6 Krissanapong Manotham1 1Molecular and Cellular Biology Unit, Department of Medicine, Lerdsin General Hospital, Bangkok, Thailand; 2Medical Sciences Program, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 3EST Laboratory, SS Manufacturing, Nonthaburi, Thailand; 4Research Division, National Cancer Institute, Bangkok, Thailand; 5Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand; 6Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Background: Doxorubicin (DOX) is the most widely used chemotherapeutic agent that has multimodal cytotoxicity. The main cytotoxic actions of DOX occur in the nucleus. The emergence of drug-resistant cancer cells that have the ability to actively efflux DOX out of the nucleus, and the cytoplasm has led to the search for a more effective derivative of this drug. Materials and methods: We created a new derivative of DOX that was derived via simple conjugation of the 3' amino group of DOX to the dexamethasone molecule. Results: Despite having a lower cytotoxic activity in MCF-7 cells, the conjugated product, DexDOX, exerted its actions in a manner that was different to that of DOX. DexDOX rapidly induced MCF-7 cell apoptosis without entering the nucleus. Further analysis showed that DexDOX increased cytosolic oxidative stress and did not interfere with the cell cycle. In addition, the conjugated product retained its cytotoxicity in multidrug resistance-1-overexpressing MCF-7 cells that had an approximately 16-fold higher resistance to DOX. Conclusion: We have synthesized a new derivative of DOX, which has the ability to overcome multidrug resistance-1-induced resistance. This molecule may have potential as a future chemotherapeutic agent. Keywords: doxorubicin, dexamethasone, drug-resistant tumor, bioconjugation, multidrug resistance, reactive oxygen specie

Recent Origin and Cultural Reversion of a Hunter-Gatherer Group

Contemporary hunter-gatherer groups are often thought to serve as models of an ancient lifestyle that was typical of human populations prior to the development of agriculture. Patterns of genetic variation in hunter-gatherer groups such as the Kung and African Pygmies are consistent with this view, as they exhibit low genetic diversity coupled with high frequencies of divergent mtDNA types not found in surrounding agricultural groups, suggesting long-term isolation and small population sizes. We report here genetic evidence concerning the origins of the Mlabri, an enigmatic hunter-gatherer group from northern Thailand. The Mlabri have no mtDNA diversity, and the genetic diversity at Y-chromosome and autosomal loci are also extraordinarily reduced in the Mlabri. Genetic, linguistic, and cultural data all suggest that the Mlabri were recently founded, 500-800 y ago, from a very small number of individuals. Moreover, the Mlabri appear to have originated from an agricultural group and then adopted a hunting-gathering subsistence mode. This example of cultural reversion from agriculture to a hunting-gathering lifestyle indicates that contemporary hunter-gatherer groups do not necessarily reflect a pre-agricultural lifestyle

The association of GSTM1 and GSTT1 polymorphisms with squamous cell carcinoma of cervix in Pakistan.

Gene deletions in GSTM1 and GSTT1 may result in tempering the activation and detoxification of several carcinogens and thereby may increase the risk of cancer pre-disposition. This study aims to investigate the clinical impact of glutathione-S-transferase GSTM1 and GSTT1polymorphisms on squamous cell carcinoma of cervix (SCCA).The GSTM1 and GSTT1 polymorphisms were analyzed in cervical cancer patients and healthy controls. Touch down multiplex polymerase chain reaction (PCR) strategy was adopted for genotyping of GSTM1 and GSTT1 polymorphisms. The null genotype of GSTM1 exhibited a significantly higher percentage in patients with SCCA (74 %) than in the control group (34.0 %). However, no significant difference was observed in the null genotype of GSTT1 among SCC patients and healthy subjects, respectively. GSTM1 exhibited a significant association with increased risk of squamous cell carcinoma (p \u3c 0.001). The odds ratio for the GSTM1 null genotype was also calculated (odds ratio 3.7484; 95 % confidence interval 1.6562-84834). This suggests that GSTM1 null genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix