From antimicrobial to anticancer peptides. A review

Abstract

Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms. Although AMPs have been essentially studied and developed as potential alternatives for fighting infectious diseases, their use as anticancer peptides (ACPs) in cancer therapy either alone or in combination with other conventional drugs has been regarded as a therapeutic strategy to explore. As human cancer remains a cause of high morbidity and mortality worldwide, an urgent need of new, selective, and more efficient drugs is evident. Even though ACPs are expected to be selective toward tumor cells without impairing the normal body physiological functions, the development of a selective ACP has been a challenge. It is not yet possible to predict antitumor activity based on ACPs structures. ACPs are unique molecules when compared to the actual chemotherapeutic arsenal available for cancer treatment and display a variety of modes of action which in some types of cancer seem to co-exist. Regardless the debate surrounding the definition of structure-activity relationships for ACPs, great effort has been invested in ACP design and the challenge of improving effective killing of tumor cells remains. As detailed studies on ACPs mechanisms of action are crucial for optimizing drug development, in this review we provide an overview of the literature concerning peptides' structure, modes of action, selectivity, and efficacy and also summarize some of the many ACPs studied and/or developed for targeting different solid and hematologic malignancies with special emphasis on the first group. Strategies described for drug development and for increasing peptide selectivity toward specific cells while reducing toxicity are also discussed.

Keywords: anticancer peptides; apoptosis induction; drug development; electrostatic interactions; membrane disruption; necrosis; tumor selectivity.

Figure 1

SVS-1 anticancer peptide disrupts the cell membrane after engaging the membrane surface and folding into a β-hairpin conformation (Sinthuvanich et al., 2012).

Figure 2

Antimicrobial and anticancer peptides (AMPs and ACPs) are expected to show different modes of action. While for the BP100 AMP is possible to establish a correlation between the minimal inhibitory concentration (MIC) and membrane charge (Alves et al., 2010) (A), for the ACP SVS-1 membrane neutralization does not occur even after cell death (B) (Gaspar et al., ; Sinthuvanich et al., 2012).

Figure 3

Anticancer peptides (ACPs) modes of action may include disruption of plasma/ mitochondrial membranes (Sinthuvanich et al., 2012), necrosis, apoptosis (van Zoggel et al., ; Xu et al., 2013), mechanisms of mediated immunity (Wang et al., 2009c), membrane receptors involvement (Leuschner and Hansel, 2005), inhibition of DNA synthesis (Ourth, 2011) and anti-angiogenic effects (Koskimaki et al., 2009). Different ACPs can act by more than one mechanism simultaneously (Wang et al., ; Xu et al., 2013).