Extensive studies have explored potential therapies against multiple myeloma (MM), whether in hospitals, universities or in private institutional settings. Scientists continue to study the mechanism(s) underlying the disease as a basis for the development of more effective treatment options. There are many therapeutic agents and treatment regimens used for multiple myeloma. Unfortunately, no cure or definitive treatment options exist. The goal of treatment is to maintain the patient in remission for as long as possible. Therapeutic agents used in combination can effectively maintain patients in remission. While these therapies have increased patient survival, a significant number of patients relapse. The off-target toxicity and resistance exhibited by target cells remain a challenge for existing approaches. Ongoing efforts to understand the biology of the disease offer the greatest chance to improve therapeutic options. Nanoparticles (targeted drug delivery systems) offer new hope and directions for therapy. This review summarizes FDA-approved agents for the treatment of MM, highlights the clinical barriers to treatment, including adverse side effects normally associated with the use of conventional agents, and describes how nanotherapeutics have overcome barriers to impede conventional treatments.
Cancer stem cells (CSCs) are cancer-initiating cells found in most tumors and hematological cancers. CSCs are involved in cells progression, recurrence of tumors, and drug resistance. Current therapies have been focused on treating the mass of tumor cells and cannot eradicate the CSCs. CSCs drug-specific targeting is considered as an approach to precisely target these cells. Clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene-editing systems are making progress and showing promise in the cancer research field. One of the attractive applications of CRISPR/Cas9 as one approach of gene therapy is targeting the critical genes involved in drug resistance and maintenance of CSCs. The synergistic effects of gene editing as a novel gene therapy approach and traditional therapeutic methods, including chemotherapy, can resolve drug resistance challenges and regression of the cancers. This review article considers different aspects of CRISPR/Cas9 ability in the study and targeting of CSCs with the intention to investigate their application in drug resistance.
With the rapid increase of multiple drug-resistant bacteria, silver nanoparticles (AgNPs) with broad-spectrum antibacterial activities have been widely applied in the treatment of bacterial infection. Meanwhile, AgNPs also have anticancer activities against different cell lines. The toxic effects of AgNPs depend on concentration, size, shape, coated materials and surrounding environments. In order to better understand the antibacterial and antitumor effects of AgNPs, various investigations have been carried out to uncover the molecular mechanism of action. This review summarizes the recent studies on the action mechanisms of AgNPs related to their antibacterial activities including collapsing cell walls, inducing reactive oxygen species, inhibiting aerobic respiration and damaging DNA and their antitumor effects including impairing mitochondria, blocking cell cycle, and activating apoptosis. In these investigations, the systematic approaches have not been extensively applied. Increasingly matured omics techniques including genomics, transcriptomic, translatomics and proteomics should be more widely explored to provide the comprehensive views of the cytotoxic effects of AgNPs to bacteria and tumor cells and thus globally illustrate the molecular mechanisms of the cytotoxicity, promoting the better medical application of AgNPs in the future.
Author(s): Ogheneochukome Lolodi, Yue-Ming Wang, William C. Wright, Taosheng Chen*
Background: Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes.
Methods: We performed a structured search of peer-reviewed literature on P450 (CYP) 3A, with a focus on CYP3A4 and CYP3A5.
Results: Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR), CYP3A4 and CYP3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands.
Conclusion: Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them.
The roles of the epidermal growth factor receptor (EGFR) signaling pathway in various cancers including breast, bladder, brain, colorectal, esophageal, gastric, head and neck, hepatocellular, lung, neuroblastoma, ovarian, pancreatic, prostate, renal and other cancers have been keenly investigated since the 1980’s. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about this pathway and how its deregulation can lead to cancer and how it may be differentially regulated in various cell types. Multiple inhibitors to EGFR family members have been developed and many are in clinical use. Current research often focuses on their roles and other associated pathways in cancer stem cells (CSCs), identifying sites where therapeutic resistance may develop and the mechanisms by which microRNAs (miRs) and other RNAs regulate this pathway. This review will focus on recent advances in these fields with a specific focus on breast cancer and breast CSCs. Relatively novel areas of investigation, such as treatments for other diseases (e.g., diabetes, metabolism, and intestinal parasites), have provided new information about therapeutic resistance and CSCs.
Background: There have been very few reports of HIV-1 subtypes and drug resistance mutations (DRMs) from Nepal which is geographically located between two high-prevalence HIV-1 infection countries, China and India.
Objective: The aim of this study was to determine prevalence of acquired and transmitted DRMs and HIV-1 subtypes in Nepal.
Methods: Thirty-five HIV-1 seropositive samples from central region of Nepal were collected in 2011. The subjects were divided into two groups, antiretroviral (ARV) drug naïve group (n=15) and antiretroviral treatment (ART) group (n=20), 90% (18/20) of them received zidovudine, lamivudine and nevirapine (AZT/3TC/NVP) regimen. HIV pol (protease and reverse transcriptase regions) nucleotide sequences were analyzed by Viroseq HIV-1 Genotyping System. Nearly full-length genomic (NFLG) sequences of 10 samples were performed.
Results: NFLG genotyping revealed that 80% of samples were infected with subtype C and 20% with recombinants (C/D/H and C/A). Phylogenetic analysis of 35 pol sequences from Nepal were subtype C. The prevalence of acquired DRMs to NNRTIs and NRTIs was 15% (3/20). DRMs to NVP, K103N and V179D, and to NRTIs were observed at 11.1% (2/18) and 5% (1/20), respectively. The prevalence of DRMs to rilpivirine for E138A/G was 5.7%. The minor protease inhibitors (PI) associated mutations (A71T/V and T74S) were observed in 5/35 (14.3%) subjects.
Conclusion: This is the first report of NFLG HIV-1 genomic sequences and DRMs from Nepal. National surveillance of HIV DRMs to ARVs and molecular epidemiology study should be done annually for better prevention and treatment of HIV infection in Nepal.
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