Targeting the microtubular network as a new antimyeloma strategy.
نویسندگان
چکیده
We identified nocodazole as a potent antimyeloma drug from a drug screening library provided by the Multiple Myeloma Research Foundation. Nocodazole is a benzimidazole that was originally categorized as a broad-spectrum anthelmintic drug with antineoplastic properties. We found that nocodazole inhibited growth and induced apoptosis of primary and multiresistant multiple myeloma cells cultured alone and in the presence of bone marrow stromal cells. Nocodazole caused cell-cycle prophase and prometaphase arrest accompanied by microtubular network disarray. Signaling studies indicated that increased expression of Bim protein and reduced X-linked inhibitor of apoptosis protein and Mcl-1(L) levels were involved in nocodazole-induced apoptosis. Further investigation showed Bcl-2 phosphorylation as a critical mediator of cell death, triggered by the activation of c-jun-NH(2) kinase (JNK) instead of p38 kinase or extracellular signal-regulated kinases. Treatment with JNK inhibitor decreased Bcl-2 phosphorylation and subsequently reduced nocodazole-induced cell death. Nocodazole combined with dexamethasone significantly inhibited myeloma tumor growth and prolonged survival in a human xenograft mouse model. Our studies show that nocodazole has potent antimyeloma activity and that targeting the microtubular network might be a promising new treatment approach for multiple myeloma.
منابع مشابه
Retrofit of Heat Exchanger Networks Considering Existing Structure: A New Targeting Procedure
A new retrofit targeting procedure, based on pinch technology has been developed. The new procedure considers existing structure of a given network and finds the most compatible configuration with the network. To achieve this aim, the procedure uses a linear programming technique that maximize the compatibility. Good compatibility between old and new networks helps to make the best use of c...
متن کاملCancer Biology and Signal Transduction Genetic and Pharmacologic Evidence That mTOR Targeting Outweighs mTORC1 Inhibition as an Antimyeloma Strategy
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, proliferation, metabolism, and cell survival, and plays those roles by forming two functionally distinct multiprotein complexes: mTOR complex 1 (mTORC1) andmTOR complex 2 (mTORC2). Deregulation of the mTOR pathway has been found in different cancers, including multiple myeloma. Agents acting onmTOR...
متن کاملAntimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101
Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable, primarily due to the treatment-refractory/resistant nature of the disease. A rational approach to this compelling challenge is to develop new drugs that act synergistically with existing effective agents. This approach will reduce drug concentrations, avoid treatment resistance, and also improve treatm...
متن کاملA Fast Strategy to Find Solution for Survivable Multicommodity Network
This paper proposes an immediately efficient method, based on Benders Decomposition (BD), for solving the survivable capacitated network design problem. This problem involves selecting a set of arcs for building a survivable network at a minimum cost and within a satisfied flow. The system is subject to failure and capacity restriction. To solve this problem, the BD was initially proposed with ...
متن کاملA New Strategy for Training RBF Network with Applications to Nonlinear Integral Equations
A new learning strategy is proposed for training of radial basis functions (RBF) network. We apply two different local optimization methods to update the output weights in training process, the gradient method and a combination of the gradient and Newton methods. Numerical results obtained in solving nonlinear integral equations show the excellent performance of the combined gradient method in ...
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 cancer therapeutics
دوره 10 10 شماره
صفحات -
تاریخ انتشار 2011