Asparagine depletion potentiates the cytotoxic effect of chemotherapy against brain tumors.
Asparagine depletion potentiates the cytotoxic effect of chemotherapy against brain tumors.
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DOI：
10.1158/1541-7786.mcr-13-0576
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Lasky JL 3rd
中科院分区：
文献类型：
--
作者：
Panosyan EH;Wang Y;Xia P;Lee WN;Pak Y;Laks DR;Lin HJ;Moore TB;Cloughesy TF;Kornblum HI;Lasky JL 3rd
Targeting amino acid metabolism has therapeutic implications for aggressive brain tumors. Asparagine is an amino acid that is synthesized by normal cells. However, some cancer cells lack asparagine synthetase (ASNS), the key enzyme for asparagine synthesis. Asparaginase (ASNase) contributes to eradication of acute leukemia by decreasing asparagine levels in serum and cerebrospinal fluid. However, leukemic cells may become ASNase-resistant by up-regulating ASNS. High expression of ASNS has also been associated with biological aggressiveness of other cancers, including gliomas. Here, the impact of enzymatic depletion of asparagine on proliferation of brain tumor cells was determined. ASNase was used as monotherapy or in combination with conventional chemotherapeutic agents. Viability assays for ASNase-treated cells demonstrated significant growth reduction in multiple cell lines. This effect was reversed by glutamine in a dose-dependent manner -- as expected, because glutamine is the main amino group donor for asparagine synthesis. ASNase treatment also reduced sphere formation by medulloblastoma and primary glioblastoma cells. ASNase-resistant glioblastoma cells exhibited elevated levels of ASNS mRNA. ASNase co-treatment significantly enhanced gemcitabine or etoposide cytotoxicity against glioblastoma cells. Xenograft tumors in vivo showed no significant response to ASNase monotherapy and little response to temozolomide (TMZ) alone. However, combinatorial therapy with ASNase and TMZ resulted in significant growth suppression for an extended duration of time. Taken together, these findings indicate that amino acid depletion warrants further investigation as adjunctive therapy for brain tumors.
