Mechanisms and Therapeutic Implications of Cell Death Induction by Indole Compounds

Abstract

Indole compounds, obtained from cruciferous vegetables, are well-known for their anti-cancer properties. In particular, indole-3-carbinol (I3C) and its dimeric product, 3,3′-diindolylmethane (DIM), have been widely investigated for their effectiveness against a number of human cancers in vitro as well as in vivo. These compounds are effective inducers of apoptosis and the accumulating evidence documenting their ability to modulate multiple cellular signaling pathways is a testimony to their pleiotropic behavior. Here we attempt to update current understanding on the various mechanisms that are responsible for the apoptosis-inducing effects by these compounds. The significance of apoptosis-induction as a desirable attribute of anti-cancer agents such as indole compounds cannot be overstated. However, an equally intriguing property of these compounds is their ability to sensitize cancer cells to standard chemotherapeutic agents. Such chemosensitizing effects of indole compounds can potentially have major clinical implications because these non-toxic compounds can reduce the toxicity and drug-resistance associated with available chemotherapies. Combinational therapy is increasingly being realized to be better than single agent therapy and, through this review article, we aim to provide a rationale behind combination of natural compounds such as indoles with conventional therapeutics.

Indoles as anticancer agents

“…Indoles have been verified to inhibit proliferation, expansion and invasion of human cancer cells [1,2,[42][43][44] . Many mechanisms of apoptosis stimulation of indole derivatives, I3C and DIM, were reported for, (a): down-regulation of anti-apoptotic gene products such as Bcl-2 (B-cell lymphoma 2) and Bcl-X L (B-cell leukemia-extra large), (b): down-regulation of the inhibitor of apoptosis proteins, e.g.…”

“…They are a very important category of compounds that play a key role in cell physiology and are probable intermediates for numerous biological reactions. Indole derivatives correspond to scores of important modules of therapeutic agents in medicinal chemistry such as anti-cancer [22] , anti-oxidant [23] , anti-rheumatoidal [24] , anti-HIV [25,26] , anti-microbial [27][28][29] , anti-inflamatory [30] , analgesic [31] , antipyretic [32] , anti-convulsant [33,34] , anthelmintic cardiovascular [35] , selective COX-2(cyclooxygenase-2) inhibitory activities [36][37][38][39] (which is an enzyme accountable for inflammation and pain) and DNA binding ability [40] . Furthermore, countless essential indole derivatives are used in disease management, for example, the non-steroidal anti-inflammatory drug indomethacin (Indocin ® ), the beta blocker pindolol (Viskin ® ) for management of high blood pressure (hypertension), the psychedelic, dimethyltryptamine (DMT) [41] and…”

“…I3C has been reported to sensitize multidrug resistant tumors to chemotherapeutic drugs without any related toxicity [1,[62][63][64] . Mechanisms of anti-cancer and chemosensitizing effects of indole compounds were summarized in Figure 9.…”

“…Chemosensitization is the progression by which compounds for example, indole compounds, I3C and DIM adapt the cellular signaling pathways leading to apoptosis and thus conquer the chemo-plus immune-resistance of well-known chemotherapeutic drugs [1,61] . I3C has been reported to sensitize multidrug resistant tumors to chemotherapeutic drugs without any related toxicity [1,[62][63][64] .…”

“…Emerging evidence also documents the ability of indoles to reverse the process of EMT via regulation of key miRNAs. An efficient induction of apoptosis and reversal of EMT not only ensures increased sensitivity to conventional drugs (chemosensitization) but also results in significantly reduced invasion and metastasis [1,[62][63][64] .…”