Investigations of calsequestrin as a target for anthracyclines: comparison of functional effects of daunorubicin, daunorubicinol, and trifluoperazine.
نویسندگان
چکیده
Anthracycline therapy is associated with a life-threatening but poorly understood cardiotoxicity. Effects of treatment are consistent with drug-induced disruption of cardiac sarcoplasmic reticulum (SR) calcium homeostasis, including inhibition of calcium release by anthracyclines. This effect, which depends on luminal SR calcium concentration, is hypothesized to involve interactions of anthracyclines with the calcium binding protein calsequestrin (CSQ). This study was designed to test the hypothesis that an interaction between CSQ and anthracyclines could be related to alterations in SR calcium release and cardiac function. The effects of the anthracycline, daunorubicin, and its metabolite daunorubicinol were compared with those of a known CSQ inhibitor, trifluoperazine (TFP). Protein fluorescence quenching studies demonstrated that TFP, daunorubicin, and daunorubicinol bind to CSQ with apparent binding affinities in the low micromolar range. The presence of calcium decreases the drug-dependent fluorescence quenching, probably because of calcium-induced CSQ conformational changes. TFP also inhibited SR calcium release. Although the TFP IC50 value is somewhat larger than for anthracyclines, the TFP effect is also dependent on luminal SR calcium concentration. In a muscle preparation, micromolar TFP decreased cardiac contractility in a manner that implicates the involvement of SR calcium and resembles the effects of anthracyclines. These data are consistent with a mechanism in which TFP or anthracyclines impair SR calcium release and cardiac function through a mechanism involving disruption of CSQ function. Such a mechanism may contribute to anthracycline cardiotoxicity.
منابع مشابه
Dmd064295 922..927
The anthracyclines doxorubicin and daunorubicin are used in the treatment of various human and canine cancers, but anthracyclinerelated cardiotoxicity limits their clinical utility. The formation of anthracycline C-13 alcohol metabolites (e.g., doxorubicinol and daunorubicinol) contributes to the development of anthracyclinerelated cardiotoxicity. The enzymes responsible for the synthesis of an...
متن کاملMultiple actions of the anthracycline daunorubicin on cardiac ryanodine receptors.
Our aim was to examine the molecular basis for acute effects of the anthracycline daunorubicin on cardiac ryanodine receptor (RyR2) channels and cardiac calsequestrin (CSQ2). Cardiotoxic effects of anthracyclines preclude their chemotherapeutic use in patients with pre-existing heart conditions. To address this significant problem, the mechanisms of anthracycline toxicity must be defined but at...
متن کاملInteraction between cardiac calsequestrin and drugs with known cardiotoxicity.
Ca(2+) regulation is coupled to critical signals in eucaryotic cells, and calsequestrin is one of the crucial components for this calcium regulation. Our previous observations of calsequestrins revealed the existence of three thioredoxin-like folds, a basic motif that often provides the platform for small molecule binding. Therefore, we have examined the previously reported trifluoperazine and ...
متن کاملDmd065110 1691..1701
The clinical efficacy of anthracyclines (e.g., doxorubicin and daunorubicin) in cancer therapy is limited by their severe cardiotoxicity, the etiology of which is still not fully understood. The development of anthracycline-induced cardiomyopathy has been found to correlate with myocardial formation and accumulation of anthracycline secondary alcohol metabolites (e.g., doxorubicinol and daunoru...
متن کاملEvidence for inhibition of growth related to compromised DNA synthesis in the interaction of daunorubicin with H-35 rat hepatoma.
The H-35 rat hepatoma is relatively insensitive to the anthracycline antibiotic, daunorubicin (DNR), requiring 0.25 microM daunorubicin for inhibition of cell proliferation by 50%. Studies were undertaken to investigate the basis for the apparent intrinsic resistance in this cell line. The relative insensitivity of the H-35 cells to DNR is not a function of metabolic inactivation of DNR to deox...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Molecular pharmacology
دوره 67 5 شماره
صفحات -
تاریخ انتشار 2005