Field Of Anticancer Therapy Research Articles

A Century of Thioxanthones: Through Synthesis and Biological Applications

The interest in the synthesis and applications of thioxanthones, dibenzo-gamma-thiopyrones, started in the beginning of the 20th century. Thioxanthones are traditionally synthesized via benzophenone, diarylthioether or diarylthioester intermediates. In recent years, more efficient and cleaner synthetic methodologies are being applied to obtain thioxanthone derivatives, especially for photochemical applications. Considering biological activities, the first thioxanthone introduced in therapy in 1945 was Miracil D, as an antischistosomal agent. Since then, the variety of studies of biological/ pharmacological activities of thioxanthones led to the discovery of new agents and to the disclosure of their mechanisms of action. Moreover, the ability to sensitize cancer cells suggested new and promising applications in chemotherapy. New antitumor derivatives are being developed by molecular modifications such as isosterism (aza-thioxanthones and aminoethylthioxanthones) or hybridation (psorospermine and acronycin analogues). The last generation of antitumor thioxanthones rendered a derivative, SR271425, with an excellent preclinical antitumor efficacy. The last decade has been excited in the research of thioxanthones with important achievements in both synthesis and biochemical applications, especially in order to dissociate the antitumor activity from the toxicity of drug candidates. Recently, thioxanthones emerged as dual inhibitors of P-glycoprotein and tumor cell growth. It is expected that in the following years new analogues with the thioxanthone scaffold emerge in the field of anticancer therapy, with enhanced antitumor activity and without serious side effects.

Pharmacogenetics and Pharmacogenomics: a Bridge to Individualized Cancer Therapy

In the past decade, advances in pharmacogenetics and pharmacogenomics (PGx) have gradually unveiled the genetic basis of interindividual differences in drug responses. A large portion of these advances have been made in the field of anticancer therapy. Currently, the US FDA has updated the package inserts of approximately 30 anticancer agents to include PGx information. Given the complexity of this genetic information (e.g., tumor mutation and gene overexpression, chromosomal translocation and germline variations), as well as the variable level of scientific evidence, the FDA recommendation and potential action needed varies among drugs. In this review, we have highlighted some of these PGx discoveries for their scientific values and utility in improving therapeutic efficacy and reducing side effects. Furthermore, examples are also provided for the role of PGx in new anticancer drug development by revealing novel druggable targets.

TIM-3 as a molecular switch for tumor escape from innate immunity

TIM-3 as a molecular switch for tumor escape from innate immunity

Abstract 5520: Thermally targeted proapoptotic peptide for cancer therapy

Abstract Peptide based therapy is a promising field of anti-cancer therapy. The biologically active therapeutic peptides, derived from an endogenous protein or designed synthetically, can inhibit or activate important cellular pathways to promote cancer cell death. The major challenges of peptide based therapy are stability and tumor-specificity of the therapeutic peptides. One of the methods to increase stability and target the therapeutic peptide to the tumor site is to utilize stimulus-responsive macromolecular carriers. We have designed a therapeutic peptide, SynB1-ELP-(KLAKLAK)2 based on the thermally responsive biopolymer, elastin-like polypeptide (ELP) and the mitochondrial membrane disrupting proapoptotic peptide, (KLAKLAK)2. Additionally, a cell penetrating peptide, SynB1 has been included in the N-terminus of this polypeptide in order to increase the polypeptide's membrane permeability. SynB1 is an 18-mer peptide derived from protegrins, which are antimicrobial peptides found in porcine leukocytes. The utilities of ELP are two-fold - 1) it is a macromolecule and therefore can provide stability to the overall polypeptide system, and 2) it is thermally responsive and therefore can be targeted to the tumor site by external application of local hyperthermia. The unique phase transition property of ELP allows it to remain soluble at physiological temperature but forces it to aggregate in response to mild hyperthermia (40 - 42 °C). Therefore, SynB1-ELP-(KLAKLAK)2 can be targeted to solid tumors by the application of local hyperthermia without being degraded before reaching the tumor. The anti-proliferative effect of SynB1-ELP-(KLAKLAK)2 was examined in MCF-7 breast cancer cells. While the polypeptide was not cytotoxic to cells at 37 °C, it killed about 40% of cells at 42 °C after 6 days with two one hour treatments. Similar treatment schedule resulted in approximately 4-fold increase in apoptosis induction at 42 °C compared to 37 °C. Confocal microscopy showed that SynB1-ELP-(KLAKLAK)2 localizes in the mitochondria which supports the mitochondrial membrane disrupting feature of the (KLAKLAK)2 peptide. In conclusion, SynB1-ELP-(KLAKLAK)2 localizes in the mitochondria and inhibits the proliferation of MCF-7 cells in combination with hyperthermia by inducing apoptosis. Further studies include determining the proapoptotic effects of SynB1-ELP-(KLAKLAK)2 in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5520.

Effect of Bcl-2 and Bax on survival of side population cells from hepatocellular carcinoma cells

To understand the role and significance of side population (SP) cells from hepatocellular carcinoma (HCC) in hepatocarcinogenesis, development, relapse and metastasis, we simulated the denutrition conditions that cancer cells experience in clinical therapy, observed the different anti-apoptosis ability of SP cells and non-SP cells under such conditions, and established the possible effects of P53, Bcl-2 and Bax on survival of SP cells. We used flow cytometry to analyze and sort the SP and non-SP cells in established HCC lines MHCC97 and hHCC. We evaluated cell proliferation by methyl thiazolyl tetrazolium (MTT) assay and investigated the expression of p53, bcl-2 and bax genes during denutrition, by RT-PCR and immunofluorescence staining. The percentage of SP cells in the two established HCC lines was 0.25% and 0.5%, respectively. SP cells had greater anti-apoptosis and proliferation ability than non-SP cells. Expression of Bcl-2 and Bax in SP and non-SP cells differed during denutrition. The former was up-regulated in SP cells, and the latter was up-regulated in non-SP cells. It may be that different upstream molecules acted and led to different expression levels of Bcl-2 and Bax in these two cell lines. There was a direct relationship between up-regulation of Bcl-2 and down-regulation of Bax and higher anti-apoptosis ability in SP cells. It may be that the existence and activity of SP cells are partly responsible for some of the clinical phenomena which are seen in HCC, such as relapse or metastasis. Further research on SP cells may have potential applications in the field of anticancer therapy.