Comprehensive Suppression of All Apoptosis-Induced Proliferation Pathways as a Proposed Approach to Colorectal Cancer Prevention and Therapy

Abstract

Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs), and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1) the signaling heterogeneity of CRC cell populations, and (2) the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents. We explored the strategy of augmenting CRC cell death by inhibiting all survival pathways induced by the pro-apoptotic agent LBH589, a histone deacetylase inhibitor: AKT, JAK/STAT, and ERK signaling. The apoptosis-enhancing ability of a cocktail of synthetic inhibitors of proliferation was compared to the effects of the natural product propolis. We utilized colorectal adenoma, drug-sensitive and drug-resistant colorectal carcinoma cells to evaluate the apoptotic potential of the combination treatments. The results suggest that an effective approach to CRC combination therapy is to combine apoptosis-inducing drugs (e.g., histone deacetylase inhibitors, such as LBH589) with agents that suppress all compensatory survival pathways induced during apoptosis (such as the cocktail of inhibitors of apoptosis-associated proliferation). The same paradigm can be applied to a CRC prevention approach, as the apoptotic effect of butyrate, a diet-derived histone deacetylase inhibitor, is augmented by other dietary agents that modulate survival pathways (e.g., propolis and coffee extract). Thus, dietary supplements composed by fermentable fiber, propolis, and coffee extract may effectively counteract neoplastic growth in the colon.

Effects of propolis and gamma‐cyclodextrin on intestinal neoplasia in normal weight and obese mice

“…B); however, there were no consistent changes in the levels of Akt/pAkt, Stat3/pStat3, and pc‐Jun/c‐Jun (data not shown). We have previously reported that propolis hyperactivates ERK signaling in CC cells in vitro . To address this discrepancy, we analyzed the response to propolis in two normal cell lines: murine fibroblast 3T3‐L1 and human epithelial intestinal CCD841CoN.…”

“…Obesity is a growing health care problem, as it is a risk factor for 10 types of cancer [5,27], including CC; however, the mechanisms for this association are still unclear [4,28]. This study is the first translational step that follows upon our in vitro findings on how propolis modulates CC cells [14,16], and it was designed to determine whether propolis influences intestinal neoplastic development in vivo, in the context of normal weight and obesity.…”

Comparative In silico Analysis of Butyrate Production Pathways in Gut Commensals and Pathogens

“…Reports have also indicated that administering butyrate can affect the production of cyclin D3 (Siavoshian et al, 2000; Tang et al, 2011), which may lead to a cessation of cell in G1 phase of cell cycle and a shift toward terminal differentiation. Butyrate is experimentally shown to be a histone deacetylase inhibitor, further emphasizing its role in reducing cell proliferation by epigenetic regulation (Bordonaro et al, 2014; Donohoe et al, 2014). Production of butyrate has been shown to decrease the pH and has been proposed to prevent the growth of pathogenic organisms like Enterococcus and Escherichia in the gut (Duncan et al, 2009; Slavin, 2013).…”

The role of pparγ and autophagy in ros production, lipid droplets biogenesis and its involvement with colorectal cancer cells modulation

“…Another hypothesis proposed by us, is that this modulation is due to an effect called apoptosis-induced proliferation. Apoptotic cells can stimulate increased cell proliferation in surviving neighboring cells [ 60 , 61 ]. Since the analysis of cell proliferation is done only in living cells, it is possible to state that the increased cell proliferation observed in cells treated with 3-MA can be a response to a stimulus received from nearby apoptotic cells.…”