Anticancer and Immunosuppressive Properties of Bacterial Prodiginines

Abstract

Bacterial prodiginines are a family of red-pigmented, tripyrrolic compounds that display numerous biological activities, including antibacterial, antifungal, antiprotozoal, antimalarial, immunosuppressive and anticancer properties. Recently, significant progress has been made in understanding the biosynthesis and regulation of bacterial prodiginines. An understanding of the biosynthesis of prodiginines will allow engineering of bacterial strains capable of synthesizing novel prodiginines through rational design and mutasynthesis experiments. Bacterial prodiginines and synthetic derivatives are effective proapoptotic agents with multiple cellular targets, and they are active against numerous cancer cell lines, including multidrug-resistant cells, with little or no toxicity towards normal cell lines. A synthetic derivative, GX15-070 (Obatoclax), developed through structure-activity relationship studies of the pyrrolic ring A of GX15, is in multiple Phase I and II clinical trials in both single and dual-agent studies to treat different types of cancer. Therefore, prodiginines have real therapeutic potential in the clinic.

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

“…In this regard, a diverse group of anionophores, lipid soluble compounds that facilitate the transport of anions across cell membranes, have recently emerged as promising anticancer compounds [8,9]. Indeed, prodigiosin, a tripyrrolic natural product with anticancer properties, represents one of the first described anionophores [10][11][12][13]. It has been reported that its biological activity is partly due to its ability to deacidify acidic compartments within cells, which may cause a drop in pHi, and therefore the onset of apoptosis in cancer cells [9,11,14].…”

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

“…Prodigiosin, a red pigment produced by bacteria as a bioactive secondary metabolite, displays numerous biological activities, including antibacterial, antifungal, antiprotozoal, antimalarial, immunosuppressive, and anticancer properties (8)(9)(10)(11)(12)(13). The prodigiosin analog obatoclax is currently in clinical trials in patients with cancer (14,15).…”

“…The prodigiosin analog obatoclax is currently in clinical trials in patients with cancer (14,15). Prodigiosin has exhibited potent cytotoxic activity against human cancer cell lines with multidrug resistance phenotypes or defects in apoptotic pathways, with much less toxicity to normal cells (12,13,16). The specific mechanisms of prodigiosin action in malignant cells have been poorly elucidated, however.…”

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

“…19,20 This tripyrrolic metabolite has been found to have potent inmunosuppresive and anticancer activities. Prodigiosin appears to cause apoptosis of cancer cells selectively, 21 and the structural analogue obatoclax is currently in clinical trials for the treatment of cancer. 22 The origin of the biological activity has yet to be unambiguously established, although there is evidence that this class of compound facilitates the co-transport of HCl [23][24][25][26][27][28] and/or the anion exchange of chloride 29,30 across lipid bilayer membranes.…”