Yuan-Chin Tsai

Bio: Yuan-Chin Tsai is an academic researcher from University of Medicine and Dentistry of New Jersey. The author has contributed to research in topics: Topoisomerase & DNA damage. The author has an hindex of 3, co-authored 6 publications receiving 736 citations.

Topoisomerase IIβ–Mediated DNA Double-Strand Breaks: Implications in Doxorubicin Cardiotoxicity and Prevention by Dexrazoxane

Abstract: Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2beta(-/-) mouse embryonic fibroblasts (MEF) compared with TOP2beta(+/+) MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIbeta (Top2beta). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2beta, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2beta, which could implicate Top2beta in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2beta in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2beta-DNA covalent complexes exposes the Top2beta-concealed DNA double-strand breaks.

Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies

Abstract: Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the beta rather than the alpha isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2beta(+) than in skin-specific top2beta-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2beta-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2beta-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2alpha-dependent. These results point to the importance of developing Top2alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.

Abstract C76: Oxazole‐containing macrocyles as selective G‐quadruplex stabilizers

Abstract: Guanine‐rich nucleic acid sequences are known to adopt G‐quadruplex structures that are stabilized by the formation of guanine tetrads. Compounds that can stabilize G‐quadruplex are known to exhibit cytotoxicity against tumor cells in culture and antitumor activity in mice with human tumor xenografts. Telomestatin, a naturally occurring macrocycle isolated from Streptomyces anulatus , is among the more specific G‐quadruplex stabilizers, binding with high specificity to G‐quadruplex DNA with no detectable binding to either duplex or single‐stranded DNA. Telomestatin has been shown to induce apoptosis of tumor cells in culture and exhibit antitumor activity in mice. The discovery of telomestatin has prompted further studies of other macrocyclic polyoxazoles that can selectively stabilize G‐quadruplex DNA and RNA. Recently the synthesis of the macrocyclic hexaoxazole HXDV was reported by our laboratory. HXDV is a 24‐membered macrocycle that stabilizes G‐quadruplexes. Despite its less complex structure, HXDV is extraordinarily selective at stabilizing G‐quadruplex versus duplex DNA, and is at least as potent as telomestatin as a cytotoxic agent. It has been determined that HXDV binds to a 24mer model human telomeric G‐quadruplex with a stoichiometry of 2:1 via a terminal capping mode of interaction. Surprisingly, HXDV was found to exhibit anti‐proliferative activity against many tumor cells independently of their telomerase status and induces strong apoptosis within 16 hours of treatment. HXDV also inhibited the progression of the cell cycle, resulting in accumulation of cells at the G2/M phase of the cell cycle. Interestingly, these studies revealed that cells were arrested at the M, rather than the G phase of the cell cycle. Unlike tubulin inhibitors, which also arrest cells at M phase, HXDV reduces the expression level of the key M phase regulator Aurora A kinase. In the aggregate, these data suggest that HXDV is a novel M phase blocker, with a possible mode of action distinct from tubulin inhibitors. Both telomestatin and HXDV have limited aqueous solubility. Replacement of one or both isopropyl groups of HXDV with an aminoalkyl side chain alters its phyiscochemical properties and enhances aqueous solubility. We also report herein the synthesis, biophysical evaluation of G‐quadruplex stabilization and selectivity, and cytotoxicity data for more than twenty 24‐membered macrocyclic polyoxazoles that have either one or two alkylamino side chains varying in length from 2–4 methylene units. One of these derivatives exhibits significant antitumor activity with IC 50 values that range from 25 to 70 nM towards human tumor cells. As the citrate salt, the solubility of some of these alkylamino derivatives increased dramatically permitting in vivo studies to evaluation their toxicity and maximum tolerated dose in mice. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C76.

Methods for treating neoplasia and for identifying compositions useful in such therapy

Abstract: Various methods for treating a patient with neoplasia are disclosed, in particular, methods using topoisomerase Ilα-preferential poisons, methods using a combination of a topoisomerase Ilβ-preferential inhibitor and a topoisomerase II poison, and methods using a combination of a topoisomerase II poison and a proteasome inhibitor are disclosed. Novel topoisomerase Ilα-preferential poisons are disclosed, particularly, several novel β-carboline derivatives are identified. Methods for identifying the novel topoisomerase Ilα-preferential poisons and methods for identifying the novel topoisomerase Ilβ-preferential inhibitors are also provided herein.

Targeting DNA topoisomerase II in cancer chemotherapy

Abstract: Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.

Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Abstract: Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

Doxorubicin pathways: pharmacodynamics and adverse effects

Abstract: The goal of this study is to give a brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and provides a summary of this active area of research. The reader is referred to recent in-depth reviews [1–4] for more detailed discussion of this important and complex pathway. Doxorubicin is an anthracyline drug first extracted from Streptomyces peucetius var. caesius in the 1970’s and routinely used in the treatment of several cancers including breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers [5–7]. A major limitation for the use of doxorubicin is cardiotoxicity, with the total cumulative dose being the only criteria currently used to predict the toxicity [4,8]. As there is evidence that the mechanisms of anticancer action and of cardiotoxicity occur through different pathways there is hope for the development of anthracycline drugs with equal efficacy but reduced toxicity [4]. Knowledge of the pharmacogenomics of these pathways may eventually allow for future selection of patients more likely to achieve efficacy at lower doses or able to withstand higher doses with lesser toxicity. We present here graphical representations of the candidate genes for the pharmacogenomics of doxorubicin action in a stylized cancer cell (Fig. 1) and toxicity in cardiomyocytes (Fig. 2), and a table describing the key variants examined so far. Open in a separate window Fig. 1 Graphical representation of the candidate genes involved in the pharmacodynamics of doxorubicin in a stylized cancer cell. A fully interactive version of this pathway is available online at PharmGKB at http://www.pharmgkb.org/do/serve?objId=PA165292163o ROS, reactive oxygen species.