Tumor-penetrating peptide fused to a pro-apoptotic peptide facilitates effective gastric cancer therapy

Abstract

KLA (sequence, KLAKLAKKLAKLAK) is a peptide which leads to programmed cell death by disrupting the mitochondrial membrane. However, low penetration in tumors greatly limits its application and efficacy. To develop a KLA-based cancer therapy, KLA-iRGD, a recombinant protein was constructed. It consists of the KLA peptide and iRGD (CRGDKGPDC), a tumor-homing peptide with high penetration into tumor tissue and cells. The conjugated KLA exhibits pro-apoptotic activity to prevent the growth of a tumor once it is inside the cell. Once KLA-iRGD is internalized in cultured tumor cells, via the activation of the receptor neuropilin-1, it spreads extensively throughout the mass of the tumor. The recombinant KLA-iRGD protein showed antitumor activity in vivo in mice and in vitro in tumor cell lines. Repeated treatment with KLA-iRGD greatly prevented tumor growth, resulting in a considerable reduction in tumor volume. According to our data, KLA-iRGD may serve as a potential anticancer agent with limited systemic toxicity and high selectivity for the treatment of MKN45 gastric cancer, which may lead to the enhancement of new targeted anticancer agents.

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

“…Anticancer peptides act as either molecularly targeted peptides, which can penetrate and directly bind to the specific cancer cell or organelle membranes, or binding peptides linking to the anticancer drugs (35)(36)(37). In cancer cells, anticancer peptides, as molecular targeting peptides, particularly in the α-helical form, penetrate the plasma membrane, the nuclear membrane and/or the mitochondrial membrane exerting pharmacological activity via different mechanisms (such as the inhibition of DNA synthesis or cell division), thus promoting cancer cell apoptosis (38)(39)(40)(41). However, binding peptides, also referred to as cancer-targeting peptides or cell-penetrating peptides, that have no anticancer property, can recognize and penetrate the cancer cell membrane (42).…”

“…Based on the mechanism of entry, therapeutic peptides are also classified into three groups based on their biological targets, including: i) Signal transduction pathways; ii) cell cycle regulation; and iii) cell death pathways (92,93). For instance, a tumor-penetrating peptide, KLA, exerts pro-apoptotic activity, which disrupts the mitochondrial membrane, leading to programmed cell death in tumors (40). In a tumor suppressor mechanism, kisspeptin-1 metastasis suppressor, a precursor for several shorter peptides, which regularly exhibits decreased expression in metastatic tumors, can suppress colonization of disseminated cancer cells in distant organs and is involved in mechanisms of tumor angiogenesis, autophagy and apoptosis regulation in breast cancer (94).…”

“…Although ACPs can induce cancer cell death and specify an expressed molecule to cellular targets, such as a cationic anticancer peptide, temporin-1CEa and melanoma cell surface-expressed phosphatidylserine (96), ACPs have limitations, including drug binding peptide delivery to cancer cell targets (97). Thus, ACPs could be developed for their high penetration into the tumor tissue and tumor cells, as well as high antitumor activity (40). While ACPs can progress from binding to killing cancer cells, in terms of molecular targeting peptides, ACPs cannot be specific or penetrated all cancer cell types, leading to the need for an addition of a binding cancer cell target, such as 'guiding missile' peptides or binding peptides.…”

“…NT4 peptides bound to GAG chains of heparan sulfate proteoglycans have a modulatory effect on the cancer cell migration and invasion ability (167). A recombinant protein consisting of iRGD (CRGDKGPDC)-conjugated KLA peptide (KLAKLAKKLAKLAK) exerts a pro-apoptotic activity and high penetration to tumor tissue and cells for gastric cancer treatment (40). Collectively, modified peptides can be developed to improve anticancer properties and the effect on the cancer targets directly.…”

Co-administration of iRGD with peptide HPRP-A1 to improve anticancer activity and membrane penetrability

“…Previous studies have shown that iRGD improves the activity and specificity of several anticancer peptides, including ATAP 15 , m(KLA) 16 , TP5 17 , CDD 18 and D (KLA) 2 19 , by conjugating with these peptides. Kazuki et al .…”