Targeting Mcl-1 for the therapy of cancer

Abstract

Introduction Human cancers are genetically and epigenetically heterogeneous and have the capacity to commandeer a variety of cellular processes to aid in their survival, growth and resistance to therapy. One strategy is to overexpress proteins that suppress apoptosis, such as the Bcl-2 family protein Mcl-1. The Mcl-1 protein plays a pivotal role in protecting cells from apoptosis and is overexpressed in a variety of human cancers. Areas covered Targeting Mcl-1 for extinction in these cancers, using genetic and pharmacological approaches, represents a potentially effectual means of developing new efficacious cancer therapeutics. Here we review the multiple strategies that have been employed in targeting this fundamental protein, as well as the significant potential these targeting agents provide in not only suppressing cancer growth, but also in reversing resistance to conventional cancer treatments. Expert Opinion We discuss the potential issues that arise in targeting Mcl-1 and other Bcl-2 anti-apoptotic proteins, as well problems with acquired resistance. The application of combinatorial approaches that involve inhibiting Mcl-1 and manipulation of additional signaling pathways to enhance therapeutic outcomes is also highlighted. The ability to specifically inhibit key genetic/epigenetic elements and biochemical pathways that maintain the tumor state represent a viable approach for developing rationally based, effective cancer therapies.

Down-Regulation of Mcl-1 by Small Interference RNA Induces Apoptosis and Sensitizes HL-60 Leukemia Cells to Etoposide

“…Of note, we found that the inhibition of Mcl-1 using siRNA also resulted in significant apoptosis in the absence of etoposide, which is in contrast to the finding of others on solid tumors (Thallinger et al, 2003, Thallinger et al, 2004. However, this observation is similar to that found on other studies on hematological malignancies (Hussain et al, 2007;Quinn et al, 2011), illustrating the important biological role of Mcl-1 in leukemic cells. In addition, siMcl-1, in combination with etoposide dramatically enhanced apoptosis compared with siRNA alone or etoposide alone.…”

“…Moreover, some reports have indicated that Mcl-1 is needed for the function of hematopoetic cell systems and survival of tumor cells (Brunelle et al, 2009;Yecies et al, 2010;Glaser et al, 2012). Studies have shown that Mcl-1 is overexpressed in various malignancies and downregulation of this protein by antisense oligonucleotide (ASO) or RNA interference (RNAi) technology induced apoptosis and sensitized tumor cells to anti-cancer agents (Chetoui et al, 2008;Skoda et al, 2008;Warr and Shore, 2008;Quinn et al, 2011;Akagi et al, 2013). Moreover, elevated expression of Mcl-1 at the time of leukemic relapse, offers a possible explanation to the role of this protein in the survival of leukemia cells after chemotherapy (Kaufmann et al, 1998).…”

BH3 Mimetics: Status of the Field and New Developments

“…Showing off-target effects, these compounds were considered as putative BH3 mimetics (5,9,(13)(14)(15)(16). Given that MCL-1 has emerged as a critical prosurvival factor in a number of malignancies and in drug resistance (17), there is an urgent need to identify MCL-1-specific BH3 mimetics (18,19). The development of small molecules capable of targeting all the main antiapoptotic BCL-2 proteins is also of clear therapeutic interest (8,(20)(21)(22).…”

Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner

“…Recently, Mcl-1 has been implicated in the regulation of mitochondrial bioenergetics and morphogenesis 8 , chemotherapy-induced senescence 9 , starvation and Ras oncogene-induced autophagy 10,11 , suggesting that its contribution to tumorigenesis may go beyond evading apoptosis. Targeting Mcl-1 is emerging as a potential therapeutic strategy [12][13][14][15][16] and therefore a deeper understanding of the mechanisms controlling Mcl-1 levels and function is of paramount importance. In comparison with other anti-apoptotic members of the Bcl-2 family, Mcl-1 exhibits some unique features including its tight regulation by complex mechanisms at the multiple levels of expression, translation and stability 17 .…”