Looking Beyond Standard Chemotherapy: Peptides in Breast Cancer Treatment

Date

2023

Authors

Vishwanatha, Jamboor K.

ORCID

0000-0002-3784-8799 (Tripathi, Amit K.)
0000-0002-0266-6020 (Vishwanatha, Jamboor K.)

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Abstract

Background: Chemotherapy is the most established method of treatment that kill fast-dividing cancer cells. However, most cancer drugs have very poor cell selectivity and kill normal cells along with cancer cells indiscriminately. Besides, the continuous use of this therapy increases the possibility of drug resistance in the body along with the chances of recurrence. The usage of peptide-based drugs to combat cancer is gaining significance in the pharmaceutical industry. The collateral damage caused to normal cells due to the use of chemotherapy, radiotherapy, etc. has given an impetus to the search for alternative methods of cancer treatment.

Candidate Protein: In the fight against cancer, newer strategies to combat cancer progression are of utmost importance. Peptides derived from naturally occurring proteins are an important strategy to identify lead molecules in the field of cancer therapeutics. Migration and invasion enhancer 1 (MIEN1) is one such candidate protein that is overexpressed in various cancers and plays an important role in cancer cell migration and invasion. Conserved regions of ITAM and prenylation motif in MIEN1 were used as a template to identify anti-cancer peptides.

In vitro Results: The two newly identified bioactive peptides (named LA3IK and RP-7) inhibited genes and proteins responsible for cancer cell migration and invasion in both MDA-MB-231 breast cancer. RNA-seq, qPCR analysis and western blots showed changes in the transcriptome and protein expression after peptide treatment. The mechanism of the action of the peptides involves the inhibition of key pathways like Epithelial-Mesenchymal transition and Epidermal Growth Factor-mediated NF-κB pathway to exert their anti-cancer activity. Interestingly, the peptides targeted the same signal transduction pathways followed by parental MIEN1 to show their anti-cancer properties. Thus, the two peptides acted as dominant negative effectors of MIEN1 activity.

In vivo results: Additionally, LA3IK and RP-7 peptide treatments induced apoptosis in mice groups bearing tumors derived from MDA-MB-231 cells as evidenced by increased levels of cleaved caspase-3 and PARP proteins in western blots. Intriguingly, the MIEN1 mRNA and protein levels were lowered in the in vivo breast cancer tumor models that remained unchanged in in vitro experiments indicating an improved therapeutic activity in the living system. The peptides did not cause any toxicity in the mice group that received peptides only, at three times the dose used during in vivo assays.

Pharmacokinetic studies: The PK studies along with the half-life determination and plasma-binding studies are underway in collaboration with the Preclinical Pharmacology Core of UT Southwestern Medical Center to identify and improve the drug-like characteristics of the MIEN1-protein derived anti-cancer peptides LA3IK and RP-7.

IP Status: An intellectual property right application has been filed for LA3IK and RP-7 in August 2022. The patent status is pending.

Acknowledgments: The work was supported by The Texas Center for Health Disparities (TCHD) under the award number: U54MD006882

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