Cancer and cardiovascular diseases are among the major causes of death in most developed countries. Most of the conventional approaches to treating cancer are quickly losing their therapeutic relevance due to the lack of tumor selectivity, drug resistance, and solubility. As such, there is a great need for the development of new therapeutic agents and treatment plans. Over the years, therapeutic peptides have provided a glimmer of hope, and they are currently being considered as a novel approach to treating a variety of diseases, including various forms of cancer.
This is because they come with a variety of advantages over normal proteins and antibodies. Some of these advantages include easy synthesis, high target selectivity, and specificity, and very low toxicity. They, however, have some drawbacks, with their stability and short half-life being among major concerns. In this piece, we will be looking at some of the therapeutic peptides receiving the most attention currently and some of the strategies being used to overcome some of the peptide limitations.
Peptides for cancer therapies
These peptides are novel and they have shown promising results when it comes to the development of anticancer agents. The existing therapeutic peptides for cancer treatments have been classified into three main groups. The classification was based mainly on their mode of operation in cancer detection or treatment. They include the following-:
Antimicrobial/Pore Forming Peptides – AMP
AMP/pore-forming peptides occur naturally in all living organisms and they portray very specific biological activities. They are considered as part of the inert immune defense system and several studies have shown that they possess highly potent antimicrobial therapeutic agents. Many of these peptides are short, they have cationic charges, and they have the ability to form amphipathic structures when placed in non-polar solvents.
AMP/pore-forming peptides have shown the ability to target cancer cell membranes as well as induce cell death among the cancerous cells through apoptosis or necrosis. In necrosis, the peptides target the negatively charged molecules on the membranes of the cancer cells. This will cause the cells to lysis. In apoptosis, the peptide will disrupt the normal activities of the mitochondrial membrane, leading to the natural death of the cells.
One of the AMP/pore-forming peptides being pursued in the designing and formulating of various cancer therapies is magainin. This is a peptide obtained from the skin of the African clawed frog. In a study conducted by Lehman et al, it was noted that this peptide was cytotoxic to cancer cells in the human bladder but not to fibroblasts. It was observed that magainin caused death to the cancer cells in the bladder through the introduction of pores in the plasma membrane.
Pluerocidin is another peptide in this category that has shown results for the treatment of breast cancer. This peptide is obtained from Winter Flounder. During the study, it was observed that they were cytotoxic to human breast cancer cells as well as mammary carcinoma cells in mice, but not to human dermal fibroblasts. These two peptides have shown promising results in disrupting the integrity of the cell membrane of the cancer cells, leading to their eventual deaths.
Buforins are also part of the AMP/pore-forming peptides which has shown incredible results in the treatment of cancer. Buforin is obtained from the stomach of Bufo gargarizans. There are two derivatives of this peptide – buforin I and buforin II. Both of them exhibit high antimicrobial activities, with buforin I displaying higher activity compared to buforin II.
Several studies have revealed that these peptides are cytotoxic against human cervical carcinoma as well as leukemia cells. They can also suppress the growth of lung cancer cells in humans. These peptides work by interacting with the gangliosides located on the plasma membranes of the cells and by introducing apoptotic extrinsic pathways in the cells to cause their eventual death.
Cell Penetrating Peptides
Cell penetrating peptides – CPPs, are the second group of therapeutic peptides currently being studied as a potential remedy to cancer. These peptides can move through the plasma membranes of the cancerous cells. They also exhibit the ability to transport a variety of cargo ranging from small molecules to large proteins. As such, they are viewed as a promising mechanism for delivering to the various cells affected by cancer.
It should be noted that cell penetrating peptides are hydrophobic in nature and their main composition is in basic residues. Studies have revealed that they play an important role in the insertion and interaction of peptides seeking access into the cell membranes. The cells can absorb them or take them up through energy-dependent or energy-independent processes. Whether or not these peptides are internalized by the cells depends on a variety of factors, including the temperatures, the cell type, the concentration of the peptides, and the cargo being transported.
A good example of a cell-penetrating peptide is the trans-activator of transcription, also known as Tat. This peptide is obtained from HIV and it has the ability to easily cross through the cell membranes. It can carry intracellular cargo across the cell membranes, with the normal cargos being nucleic acid, small inferring RNA, therapeutic agents, liposomes, and oligonucleotides. In a recent study by Lim et al, the researchers managed to design a novel CPP which they called BR2. This is a 17 AA type peptide derived from the CPP motif for buforin II.
The studies showed that the peptide was cytotoxic against breast cancer cells, human colon cancer cells, and mouse melanoma cells. The studies also found that it was not cytotoxic to human fibroblasts, human keratinocytes, and mouse fibroblasts. It was also discovered that the peptide could interact with gangliosides which are usually found inside the cell membranes of the three cancer cells.
Tumor Targeting Peptides
The third group of therapeutic peptides is the Tumor Targeting Peptides – TTP. Just as the name suggests, these peptides have the ability to target the biomarkers that are usually expressed on the membranes of the tumor cells. One example of TTP is RGD which contains the sequence Arg-Gly-Asp. This peptide has the ability to recognize and bind itself to integrin expressed on various cancer cells such as breast cancer cells, lung cancer cells, ovarian cancer cells, brain tumors, and melanoma.
As such, RGD can be easily used as a drug delivery system because it is easy to internalize into the cells. When the RGD peptide was fused onto the surface of a sterically stabilized liposome, it was observed that doxorubicin – the hydrophobic polymer located on the peptide’s surface increased the efficacy of the peptide when it was exposed to human melanoma cells grown in vitro and tumors grown in vivo in mice.
The other TPP peptide is the NGR which comes with the Asn-Gly-Arg sequence. This peptide can bind to amino peptides normally found in higher concentrations on the endothelial tumor cells such as those in gastric cancer, non-small lung cancer cells, and pancreatic cancer. A study conducted by Chan et al fused this peptide with PEGylated LPD to facilitate the intracellular delivery of doxorubicin or myc-siRNA in fibrosarcoma cell xenografts. It was observed that the peptide-induced apoptosis in the cancerous cells in both in vitro and in vivo. A major observation here was that the delivery greatly hindered the growth of the cancerous cells.
How to overcome peptide limitations
Various strategies have been advanced for overcoming the various peptide limitations in the development of drugs as well as cancer therapies. One such limitation is poor cell permeability. To overcome this limitation, various cell-penetrating peptides have been developed with the aim of enhancing the intracellular delivery of the peptides. The Tat peptides, on the other hand, was conjugated with various pro-apoptotic peptides. When the conjugated peptide was taken by human breast cancer cells and mouse melanoma, it was observed that endogenous caspase-3 was activated.
This was then cleaved to the Tat peptide leading to the release of the pro-apoptotic peptides which eventually caused numerous deaths of the cancer cells. To improve the selectivity as well as the specificity of the Tat peptide, it was further conjugated with BRBP1 peptide which has been proven to have an extremely high affinity for the human breast cancer cells. These peptides have also been proven to have the ability to greatly reduce the viability as well as the migratory capacity of 231-BR cells known to metastasize to the brain.
Multidrug resistance is another challenge that has hampered the use of conventional cancer treatments. Some of the cancer treatments can no longer be relied upon because they have lost their effectiveness on tumors that have a resistant phenotype. Recently, elastin-like polypeptides – ELPs, have been considered as a means of overcoming drug resistance in some tumor cells. In a study featuring Tat peptides fused with N-terminal, a tetrapeptide linker, ELP, and a C-terminal, it was observed that it was possible to overcome the efflux pumps normally experienced in uterine sarcoma cells. These and similar such interventions are still being explored to find a safe and lasting solution to the menace of drug resistance.
