Abstract
In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE) - based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination resulted in synergistic cytotoxicity, and the cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose) polymerase (PARP) and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. We further show that ABT-737 caused endoplasmic reticulum (ER) stress with increased GRP78 and phosphorylated eIF2α protein levels. Moreover, treatment with ABT-737 increased the intracellular calcium levels, an effect which was enhanced by 9.2.27PE, which as a single entity drug had minimal effect on calcium release from the ER. In addition, silencing of Mcl-1 by short hairpin RNA (shRNA) enhanced the intracellular calcium levels and cytotoxicity caused by ABT-737. Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model, supporting further investigations of this particular drug combination.
Highlights
Surgical treatment of primary melanoma is associated with high curative rate
The Bcl-2 family proteins may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies, and spontaneous cellular immune responses against the Bcl-2 family proteins have been identified as frequent features in cancer patients [28]
These observations underscore that the Bcl-2 family proteins are natural targets for the immune system, these proteins may serve as an important target for anti-cancer immunotherapeutic strategies [28]
Summary
Surgical treatment of primary melanoma is associated with high curative rate. if the melanoma has progressed to distant metastases, treatment failure is common due to high resistance to current treatment modalities [1,2]. PLX4032, a selective BRAFV600E inhibitor, caused partial or complete response in early clinical trials [4,5], the patients eventually develop resistance. The MEK inhibitors PD0325901 and AZD6244 have been evaluated in early clinical trials, without improvement in the progression-free survival compared to Temozolomide [6], an oral form of the chemotherapeutic drug Dacarbazine used to treat melanoma patients. These results underscore the importance of developing new drugs with yet different mechanisms of action
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