The intestinal microbiota is responsible for the production of a range of bioactive metabolites, and some of them have anticancer properties against various forms of cancer [1]. Reducing microbial community diversity in cancer patients is typically associated with reduced production of antiproliferative metabolites, suggesting a possible role in tumor growth [2]. An example of such a microbial metabolite is lithocholic acid (LCA), a secondary bile acid that has been found to affect crucial tumor events. LCA reverses epithelial-mesenchymal transition (EMT), controls the metabolism of cancer cells, promotes antitumor immune function, and inhibits the proliferation of tumor cells [2]. Moreover, LCA at high doses can trigger apoptosis in cancer cells by cytotoxic pathways [3], [4]. LCA acts in a wide variety of biological activities. LCA was found to bind and activate the vitamin D receptor (VDR) and thus affect cell proliferation and differentiation-related gene expression [5]. LCA also has antimicrobial action, which could be implicated in the modulation of gut microbiota composition [6]. Its anticancer activity has been evidenced by its anti-proliferative and pro-apoptotic action against diverse human cancer cell lines [7]. In addition, LCA may block proteasome function, which could interfere with mechanisms of cancer cell survival [8]. It can also be a membrane-disruptive agent by pore formation in lipid bilayers [9]. Aside from its anticancer activity, LCA has also been shown to increase lifespan and decelerate age-related cellular senescence in model organisms [10].

LCA exhibits selective cytotoxicity toward different cancer cell lines, such as human neuroblastoma, prostate, breast, and rat glioma cells, but very little cytotoxicity toward normal cells when administered at the same concentration [11], [12]. Selective cytotoxicity is mediated largely by induction of intrinsic and extrinsic pathways of apoptosis, partly caspase-dependent. In prostate cancer PC-3 cells, LCA also induces endoplasmic reticulum (ER) stress via a pathway involving phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) [13]. Furthermore, LCA induces autophagy in autophagy-proficient PC-3 cells, suggesting that its anticancer activity is mediated by a complex interplay of cell death mechanisms and stress-adaptive responses [13].

LCA induces oxidative stress and apoptosis by multiple mechanisms, including reducing the antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2) and activation of the bile acid sensor TGR5 [14]. In addition to the maintenance of redox homeostasis, LCA regulates mitochondrial oxidative phosphorylation and has the capacity to enhance antitumor immune response [15]. It represses cancer cell growth and metastasis, which justifies its use as an agent of therapy. Interestingly, LCA levels in breast cancer tissue inversely relate to Ki-67 expression—a known marker of cell proliferation—suggesting its role in constraining tumor growth [16].

LCA is pharmacologically active due to its wide-spectrum antibacterial and antifungal activities, as well as due to its α-2,3-sialyltransferase inhibitory activity [17]. Its therapeutic potential is further enhanced through the induction of VDR expression in an intense manner and through its previously demonstrated anticancer activity [17]. In addition to its anticancer activity itself, LCA also exhibits immunomodulatory activity in vivo. LCA treatment significantly inhibited the expression of proinflammatory cytokines, such as Tumor Necrosis Factor alpha (TNF alpha), Interleukin (IL)-6, and IL-1, in the colonic mucosa in murine models, reducing intestinal inflammation [17]. Additionally, LCA fortified the integrity and barrier protection of the colonic epithelium, which suggests its therapeutic application for gastrointestinal disease [17]. Kovács et al.[1] found that the cytostatic action of LCA is mediated by mechanisms of oxidative and nitrosative stress. That is, LCA suppresses the NRF2/Keap1 antioxidant defense pathway, resulting in the induction of inducible nitric oxide synthase (iNOS) and increased nitrosative stress. These actions are promoted by the activation of bile acid-activated receptors, including TGR5 and constitutive androstane receptor (CAR)[1]. Interestingly, LCA-induced oxidative stress has been associated with enhanced survival in breast cancer patients, and suppression of this pathway is prevalent in triple-negative breast cancer (TNBC) [1]. The complex roles of LCA in carcinogenesis with particular reference to its molecular basis and therapeutic application are reviewed here.