PNC 27 peptide is the new miracle drug that fights leukemia and colon cancer cells. Scientists agree that this work also concluded that the peptide does not affect the proliferation of normal tissues which is in-line with the current thinking about the peptide in cancer therapy \[[@CR15]\].
What is PNC 27 Peptide?
In another approach, a conjugated liposome loaded with a modified peptide (i.e. pGpY) was prepared. This particular study also indicated a strong affinity for the peptide in the formulation \[[@CR16]\]. A recent study also carried out using liposomes showed that incorporation of the peptide into liposomes enhances its internalization by cancer cells via receptor-mediated endocytosis \[[@CR17]\].
Another approach is to form nanosized colloidal vehicles that are able to protect the loaded drugs from the hostile environment of the plasma and at the same time have the ability to deliver them to the target site \[[@CR18], [@CR19]\]. Polymeric micelles and dendrimers are among the most widely used carriers in cancer nanomedicine. These particles have been used to form nanoparticles loaded with both natural and modified peptides \[[@CR20]–[@CR22]\]. The most potent and selective peptide identified to date is the AMP, which is derived from the C-terminus of the MHC Class I associated protein human leukocyte antigen-B-48 (HLA-B-48).
PNC 27 Peptide Uses
This cationic AMP has a sequence, Arg-Lys-Asp-Lys-Asp-Cys-Pro-Arg-Phe-Tyr-Glu-Phe-Cys-Pro-Arg-Phe-Tyr-Glu-Phe-Cys- (i.e. KDKCPKRFQY). This peptide exhibits a significant cytotoxic effect against human AML cell lines and patient derived CD34 + cells. Using the AMP conjugated to a cell penetrating peptide, it has been shown that the peptide specifically targets AML cells and induces apoptosis. More specifically, the AMP-pHLA-B-48 shows significant anti-tumor activity in AML patients’ cells while, showing no adverse side effects.
This is significant in that the drug showed the same therapeutic effect in AML cell lines that express and do not express HLA-B-48. This indicates that the AMP targets AML cells expressing the MHC Class I peptide HLA-B-48 rather than non-expressing AML cells \[[@CR23]\]. Recently, in a study designed to develop an effective strategy to target malignant cells for AML treatment, a series of peptides, which included the KDKCPKRFQY sequence (KDKC peptide) was shown to possess significant cytotoxic activity against both acute and chronic AML cell lines.
The mechanism of action of this AMP was based on the induction of apoptosis \[[@CR24]\]. Other studies have also demonstrated that the KDKC peptide has very potent anti-tumor activity against AML cell lines. This suggests that this AMP can be used as a therapeutic approach for the treatment of AML \[[@CR25]\]. The second most potent peptide that has been discovered in several studies is a linear 13 amino acid peptide which has been designated as the p13 peptide (LLFVPQTVPSKSF). This peptide was found to exhibit apoptotic effects in different leukaemia cell lines including HL60, Jurkat and K562 cells.
In addition, the peptide is effective in promoting cell death in AML and AML-M2 cells via apoptosis and inducing autophagy in AML-M2 cells. Moreover, the peptide induces death receptor 5 and 7-mediated apoptosis and is able to sensitize the cells to chemotherapy. As a result, the peptide and the combination of the peptide with chemotherapy could be potentially used to treat AML \[[@CR26]\]. The third most potent peptide to-date is termed the d5 peptide (LLFVPQTR) \[[@CR27]\]. This peptide was also shown to be active against AML cell lines such as U937 and HL60 cells \[[@CR28]\]. Peptide inhibitors of cellular functions {#Sec4} ======================================== The second and third approaches in anticancer therapy involves the use of peptide inhibitors that can inhibit the tumorigenic functions of specific proteins such as proteases \[[@CR29]\], inhibitors of the cell cycle checkpoints, such as protein kinase C (PKC) inhibitors \[[@CR30]\] and small molecules inhibitors of the signal transduction pathways that promote the growth of cancer \[[@CR31]\]. Peptides that inhibit protein activities have also been reported to have anti-tumor effects.
For example, an approach to block angiogenesis could be based on the use of a peptide to inhibit vascular endothelial growth factor. This growth factor induces proliferation, migration and formation of new blood vessels \[[@CR32]\]. In addition, a number of small molecules inhibitors have been identified that target different proteins or signaling pathways to prevent cancer development \[[@CR33]\].
Interestingly, the FDA-approved tyrosine kinase inhibitors which inhibit specific tyrosine kinases, can sometimes induce the development of therapy-resistant cancer by activating alternative signaling pathways \[[@CR34]\]. As a result, novel therapies to combat cancer resistance have been developed. A peptide or peptidomimetic approach can have beneficial effects in some of these situations. Thus, as an alternative to small molecules inhibitors, peptides or peptidomimetics can block the action of kinases by direct binding to the protein or by preventing its interaction with other proteins \[[@CR35], [@CR36]\]. One of the peptide-based inhibitors, which has been used to inhibit protein tyrosine kinase is the peptidyl-prolyl cis-trans isomerase (PPIase) inhibitor, which has been shown to be active against a wide variety of cancers including leukemia \[[@CR37]\].
In addition, several peptidomimetic inhibitors of tyrosine kinases have been identified which can prevent autophosphorylation or phosphorylation of the receptor by a drug-bound inhibitor \[[@CR38]\]. A few recent reviews have addressed the use of peptides or peptidomimetics to target tyrosine kinases and their signaling \[[@CR39]–[@CR42]\]. There have also been several reviews which have discussed the use of small molecules and peptides to inhibit other proteins including the epidermal growth factor receptor (EGFR) \[[@CR43]–[@CR46]\]. Several of the protein kinases (e.g. PDK1) which promote tumor cell survival are activated in an autophosphorylation manner \[[@CR47]\].
This is an important mechanism in promoting cell survival by inhibiting apoptosis. Consequently, peptides and small molecules inhibitors which can block the PDK1/Akt1 signaling pathway could potentially inhibit cell growth and/or induce cell death. For example, a peptide inhibitor of the PDK1, which has an ability to block Akt1 autophosphorylation and phosphorylation of downstream substrates such as GSK-3beta and MDM2. This peptide inhibits Akt1 kinase activity and its downstream signaling. This peptide can disrupt the interaction of Akt1 with its binding partners thus preventing the PDK1/Akt1/GSK-3beta complex from being formed \[[@CR48]\]. Another peptide or peptidomimetic approach involves the inhibition of the cell cycle checkpoint protein kinase 2 (CDK2) which is highly expressed in AML cells. The use of a peptide inhibitor of CDK2 which has been loaded into liposomes has been shown to target AML cells via receptor-mediated endocytosis.
PNC 27 Peptide Uses
This particular approach was also effective against the non-AML AML cell line NB4 \[[@CR16]\]. Other protein kinases that have been shown to promote cell survival in AML include the Akt and the S6 protein kinases. The most potent inhibitor of the S6 kinase, which has been reported, is also known as pamolin A, is a highly specific inhibitor of the activity of S6K1 and its splice variant, S6K2 \[[@CR49]\]. However, this inhibitor also affects the mammalian target of rapamycin (mTOR) kinase as well as the Akt kinase \[[@CR50]\]. In addition, a novel approach to target Akt by identifying an inhibitory fragment of Akt has also been described \[[@CR51]\].
The identified peptide shows a selectivity to inhibit Akt and the T293A mutant of Akt2 while, it has no effect on the wild type Akt2 protein. Moreover, this peptide can suppress the PI3K pathway by suppressing the phosphorylation of p85 subunit of PI3K \[[@CR51]\]. Thus, peptide-based inhibitors can be used to inhibit the Akt kinase and this approach has been suggested to have therapeutic potential in AML. Cancer therapeutics targeting oncogenic proteins {#Sec5} ================================================= A number of proteins including the tyrosine kinase and transcription factors have been shown to be aberrantly expressed in AML and consequently, these proteins have been targeted to inhibit tumorigenesis. The first cancer cell-based targets which have been used to treat AML include transcription factors. This involves the use of proteins which are expressed in several types of tumors such as the retinoblastoma protein, E2F1 and the MYC oncogene. A number of reviews have addressed this topic including recent review by Czabotar et al. \[[@CR52]\].
