Pharmacologic modulation of serine/threonine phosphorylation highly sensitizes PHEO in a MPC cell and mouse model to conventional chemotherapy

Autor: Karel Pacak, Jie Lu, Zhengping Zhuang, Jeffrey Chiang, Lucia Martiniova, Marcelino Bernardo, Russell R. Lonser
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Threonine
Cell
Adrenal Gland Neoplasms
Drug Evaluation
Preclinical
Oncology/Oncology Agents
lcsh:Medicine
Pheochromocytoma
Pharmacology
Serine
Mice
Physics/Atomic and Molecular Physics
Serine/Threonine Phosphorylation
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Temozolomide
medicine
Animals
Humans
Cytotoxic T cell
Protein Phosphatase 2
Neoplasm Metastasis
Phosphorylation
Physics/Nuclear Physics
Radiology and Medical Imaging/Computer Tomography
lcsh:Science
Protein Kinase Inhibitors
Oncology/Neuro-Oncology
Multidisciplinary
Chemistry
lcsh:R
Radiology and Medical Imaging/Magnetic Resonance Imaging
Cancer
Drug Synergism
Protein phosphatase 2
medicine.disease
Dacarbazine
Disease Models
Animal
medicine.anatomical_structure
Drug Resistance
Neoplasm
Radiology and Medical Imaging/PET and SPECT Imaging
lcsh:Q
Radiology and Medical Imaging/Radionuclide Imaging
Research Article
Zdroj: PLoS ONE, Vol 6, Iss 2, p e14678 (2011)
PLoS ONE
ISSN: 1932-6203
Popis: Background The failure of cytotoxic cancer regimens to cure the most drug-resistant, well-differentiated solid tumors has been attributed to the heterogeneity of cell types that differ in their capacities for growth, differentiation, and metastases. We investigated the effect of LB1, a small molecule inhibitor of serine/threonine protein phosphatase 2A (PP2A), on its ability to inhibit a low growth fraction and highly drug-resistant solid neuroendocrine tumor, such as metastatic pheochromocytoma (PHEO). Subsequently, we evaluated the increased efficacy of chemotherapy combined with LB1. Methodology/Principal Findings The effect of LB1 and temozolomide (TMZ), a standard chemotherapeutic agent that alone only transiently suppressed the growth and regression of metastatic PHEO, was evaluated in vitro on a single PHEO cell line and in vivo on mouse model of metastatic PHEO. In the present study, we show that metastatic PHEO, for which there is currently no cure, can be eliminated by combining LB1, thereby inhibiting PP2A, with TMZ. This new treatment approach resulted in long term, disease-free survival of up to 40% of animals bearing multiple intrahepatic metastases, a disease state that the majority of patients die from. Inhibition of PP2A was associated with prevention of G1/S phase arrest by p53 and of mitotic arrest mediated by polo-like kinase 1 (Plk-1). Conclusions/Significance The elimination of DNA damage-induced defense mechanisms, through transient pharmacologic inhibition of PP2A, is proposed as a new approach for enhancing the efficacy of non-specific cancer chemotherapy regimens against a broad spectrum of low growth fraction tumors very commonly resistant to cytotoxic drugs.
Databáze: OpenAIRE
Externí odkaz: