Anticancer Activities of Surfactin and Potential Application of Nanotechnology Assisted Surfactin Delivery

Abstract

Surfactin, a cyclic lipopeptide biosurfactant produced by various strains of Bacillus genus, has been shown to induce cytotoxicity against many cancer types, such as Ehrlich ascites, breast and colon cancers, leukemia and hepatoma. Surfactin treatment can inhibit cancer progression by growth inhibition, cell cycle arrest, apoptosis, and metastasis arrest. Owing to the potent effect of surfactin on cancer cells, numerous studies have recently investigated the mechanisms that underlie its anticancer activity. The amphiphilic nature of surfactin allows its easy incorporation nano-formulations, such as polymeric nanoparticles, micelles, microemulsions, liposomes, to name a few. The use of nano-formulations offers the advantage of optimizing surfactin delivery for an improved anticancer therapy. This review focuses on the current knowledge of surfactin properties and biosynthesis; anticancer activity against different cancer models and the underlying mechanisms involved; as well as the potential application of nano-formulations for optimal surfactin delivery.

Keywords: anticancer; biosurfactant; lipopeptide; nano-formulation; surfactin.

Figure 1

(A) Primary structure of surfactin, n = 9–11 (indicating the number of CH2 group in the peptide chain). (B) Chemical structure of surfactin. Seven amino acids are arranged in the cyclic ring connected with a fatty acid (β-hydroxy) of the chain lengths 12–16 carbon atoms to form a cyclic lactone ring.

Figure 2

Three-dimensional structure of surfactin. The backbone is represented by the gray atoms. Seven amino residues (1–7) are presented. Hydrophobic residues (2, 3, 4, 6, and 7) are represented by white atoms, where the lipidic chain attaches. The black and dark gray atoms represent acidic residues 1 and 5, respectively.

Figure 3

Schematic diagram of surfactin synthetase complex for biosynthesis of cyclic surfactin. Surfactin synthetase complex is composed of three-modular SrfA, three-modular SrfB, mono-modular SrfC and SrfD subunits, which is used to synthesize seven amino acids of surfactin. The peptide chain is elongated from left to right until the linear product is cyclized by TE domain.

Figure 4

Proposed mechanisms involved in in vitro anticancer activity of surfactin. The anticancer activity of surfactin is associated with growth inhibition, cell cycle arrest, cell death (apoptosis), and metastasis inhibition. Surfactin treatment can inhibit cancer cell viability by inactivating the cell survival signaling pathways. Besides, surfactin regulates cell cycle-regulatory proteins, which are pivotal for cell cycle phase transition to block the proliferation of cancer cells. The apoptotic effect (intrinsic mitochondrial/caspase pathway) of surfactin is mediated by two different pathways that are triggered by high intracellular ROS formation, namely ERS/[Ca²⁺]_i/ERK1/2 and JNK/ΔΨm /[Ca²⁺]_i/Bax-to-Bcl-2 ratio/cyt c pathways. Surfactin-induced apoptosis is also associated with the changes in phospholipids composition that leads to a significant decrease in unsaturated degree of cellular fatty acids. Apart from these, surfactin also inhibits the invasion, migration and colony formation of cancer cells in the virtue of MMP-9 expression change that involves the inactivation of NF-κB, AP-1, PI3K/Akt, and ERK1/2 signaling pathways.

Figure 5

SEM images of (A) PVA (10%, w/v) loaded with (B) 0.5% (w/v), (C) 1.0% (w/v), and (D) 1.5% (w/v) surfactin (Adopted from Ahire et al., 2017). Reprinted with permission. Copyright (2017) Elsevier.

Figure 6

SEM images of surfactin nanomicelle in distilled water (A) and PBS (B) (pH 7.4) (Adopted from Nozhat et al., 2012). Reprinted from open access journal, Copyright (2012) Zahra Nozhat et al.

Figure 7

Proposed micelle formation using surfactin as building blocks.