In addition to inactivation of Notch we found that

In addition to inactivation of Notch, we found that the combination of BTZ and GSI-I downregulated ERK phosphorylation in ALK+ ALCL cells, and we speculate this may occur through the inhibition of upstream regulators of the ERK pathway. These findings emphasize the functional complementation of the two drugs in the inhibition of ERK signaling. Recent studies have revealed the intersection between regulatory circuits that control apoptosis, autophagy and cell homeostasis. For example, signaling pathways involving PI3-kinase, mTOR kinases and AKT are stimulated by survival signals to hinder apoptosis; PI3K signaling is downregulated in the absence of survival signals, leading to apoptosis [[51], [52], [53]]. Notably, a cross-talk between the ERK and AKT cascades has also been recently described [54]. We found that the combination of BTZ and GSI-I could reduce AKT signaling; the level of phosphorylated AKT was reduced by the BTZ and GSI-I combination, suggesting a role in AKT signaling to downregulate the threshold of apoptosis. Recently, the relationship between ERK and AKT cascades was reported [55]. Therefore, downregulation of both the AKT/mTOR and ERK signaling pathways may be more fatal than interruption of either pathway alone in ALK + ALCL. The c-Jun transcription factor plays an important role in the progression of many hematological diseases [56,57]. A previous study showed that BTZ upregulated the expression of p-JNK, a critical upstream messenger of c-Jun [58]. BTZ-mediated induction of apoptosis in leukemia HC-030031 has also been linked to JNK and p38 MAPK activation [59]. Our results showed that the combination of BTZ with GSI-I led to a significant increase in p-JNK and p-c-Jun, consistent with their activity as inhibitors of cell apoptosis, and these increases were marked compared with single treatments alone. Together these results indicate the synergic effect of the combination treatment on stress-related ALK+ ALCL apoptosis cascades. In conclusion, our study provides novel evidence that GSI-I in combination with BTZ synergistically inhibited ALK+ALCL cells in vitro and ALK+ALCL tumor growth in vivo. These findings may provide a new strategy for the clinical treatment of ALK + ALCL.
Introduction Alzheimer's disease (AD) is the most common form of dementia that causes problems with memory, thinking and behavior in the elderly. These problems can become so severe over time that the patients will not be able to participate in conversation and to respond to their environment. AD is the sixth leading cause of death across all ages in the United States. An estimated 5.3 million Americans have AD and causing $226 billion in cost to the nation in 2015 [1]. As the elderly population continues to grow, the prevalence of AD will increasingly be a major burden to the nation's health care system. It is known that γ-secretase is one of the critical enzymes required for the generation of Aβ peptides. Accumulation and deposition of Aβ plaques leads to the damage and death of neurons, which is correlated with severity of AD [2]. Thus, inhibition of γ-secretase is considered to be a disease-modifying approach for this disorder [3]. Small-molecule GSIs have been shown to lower levels of plasma, cerebrospinal fluid (CSF), and cortical Aβ peptides in the animal models [4]. A review of recent advances in the identification of GSIs was published in a Journal of Medicinal Chemistry perspective [5]. The same review also discussed the application of GSIs beyond AD, such as for the treatment of leukemia [6] and breast cancer [7]. The previously published research from our group identified novel series of arylsulfonamides as γ-secretase inhibitors. Josien and Pissarnitski et al. reported N-arylsulfonamides as orally active GSIs (Structure I, Fig. 1) [8], [9]. Li et al. demonstrated that adding a hydroxyl group on piperidine ring can further reduce the CYP inhibition while retain the GSI activity (Structure II, Fig. 1) [10].