Abstract
Metastatic melanoma has poor prognosis and is refractory to most conventional chemotherapies. The alkylating agent temozolomide (TMZ) is commonly used in treating melanoma but has a disappointing response rate. Agents that can act cooperatively with TMZ and improve its efficacy are thus highly sought after. The BH3 mimetic ABT-737, which can induce apoptosis by targeting pro-survival Bcl-2 family members, has been found to enhance the efficacy of many conventional chemotherapeutic agents in multiple cancers. We found that combining TMZ and ABT-737 induced strong synergistic apoptosis in multiple human melanoma cell lines. When the drugs were used in combination in a mouse xenograft model, they drastically reduced tumor growth at concentrations where each individual drug had no significant effect. We found that TMZ treatment elevated p53 levels, and that the pro-apoptotic protein Noxa was elevated in TMZ/ABT-737 treated cells. Experiments with shRNA demonstrated that the synergistic effect of TMZ and ABT-737 was largely dependent on Noxa. Experiments with nutlin-3, a p53 inducer, demonstrated that p53 induction was sufficient for synergistic cell death with ABT-737 in a Noxa-dependent fashion. However, p53 was not necessary for TMZ/ABT-737 synergy as demonstrated by a p53-null line, indicating that TMZ and ABT-737 together induce Noxa in a p53-independent fashion. These results demonstrate that targeting anti-apoptotic Bcl-2 members is a promising method for treating metastatic melanoma, and that clinical trials with TMZ and Bcl-2 inhibitors are warranted.
Highlights
The incidence of metastatic melanoma has increased rapidly in recent decades, but there has been little improvement in therapeutic efficacy [1]
Naumann and coworkers found that apoptosis is the major mode of death for melanoma cells exposed to TMZ, but that it requires time for double-stranded DNA breaks to occur, and apoptosis is not observed with short treatment times (72 h or less) [9]
ABT-737 synergistically induces apoptosis in melanoma cells when combined with temozolomide
Summary
The incidence of metastatic melanoma has increased rapidly in recent decades, but there has been little improvement in therapeutic efficacy [1]. Dacarbazine is the standard firstline treatment for advanced melanoma, but its response rate is poor, averaging around 15% with no improvement in survival duration [1,2]. Whether and to what degree TMZ induces apoptosis in melanoma cells is a subject of debate. Some studies have shown that clinically relevant doses of TMZ do not induce significant levels of apoptosis in melanoma cells in vitro, potentially explaining its poor clinical response rate [7,8]. Naumann and coworkers found that apoptosis is the major mode of death for melanoma cells exposed to TMZ, but that it requires time for double-stranded DNA breaks to occur, and apoptosis is not observed with short treatment times (72 h or less) [9]. Enhancing the apoptotic potential of TMZ, for example by triggering apoptosis under situations in which cell cycle arrest would predominate, is a promising means of enhancing the efficacy of TMZ in melanoma patients
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