Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches

Abstract

Chemotherapy is the main treatment for most early-stage cancers; nevertheless, its efficacy is usually limited by drug resistance, toxicity, and tumor heterogeneity. Cell-penetrating peptides (CPPs) are small peptide sequences that can be used to increase the delivery rate of chemotherapeutic drugs to the tumor site, therefore contributing to overcoming these problems and enhancing the efficacy of chemotherapy. The drug combination is another promising strategy to overcome the aforementioned problems since the combined drugs can synergize through interconnected biological processes and target different pathways simultaneously. Here, we hypothesized that different peptides (P1–P4) could be used to enhance the delivery of chemotherapeutic agents into three different cancer cells (HT-29, MCF-7, and PC-3). In silico studies were performed to simulate the pharmacokinetic (PK) parameters of each peptide and antineoplastic agent to help predict synergistic interactions in vitro. These simulations predicted peptides P2–P4 to have higher bioavailability and lower Tmax, as well as the chemotherapeutic agent 5-fluorouracil (5-FU) to have enhanced permeability properties over other antineoplastic agents, with P3 having prominent accumulation in the colon. In vitro studies were then performed to evaluate the combination of each peptide with the chemotherapeutic agents as well as to assess the nature of drug interactions through the quantification of the Combination Index (CI). Our findings in MCF-7 and PC-3 cancer cells demonstrated that the combination of these peptides with paclitaxel (PTX) and doxorubicin (DOXO), respectively, is not advantageous over a single treatment with the chemotherapeutic agent. In the case of HT-29 colorectal cancer cells, the combination of P2–P4 with 5-FU resulted in synergistic cytotoxic effects, as predicted by the in silico simulations. Taken together, these findings demonstrate that these CPP6-conjugates can be used as adjuvant agents to increase the delivery of 5-FU into HT-29 colorectal cancer cells. Moreover, these results support the use of in silico approaches for the prediction of the interaction between drugs in combination therapy for cancer.

A Small Sugar Molecule with Huge Potential in Targeted Cancer Therapy

“…Peptide combinations with PTX and DOX have been shown not to be effective against MCF-7 and PC-3 cancer cells compared to drug treatment. However, as expected in silico, the combination of peptides with 5-FU produced synergistic cytotoxic effects against HT-29 colorectal cancer cells [ 281 ].…”

New Perspective for Using Antimicrobial and Cell-Penetrating Peptides to Increase Efficacy of Antineoplastic 5-FU in Cancer Cells

“…The overarching goal is to significantly enhance the effectiveness of chemotherapy, while simultaneously mitigating its associated side effects and the potential development of drug resistance [20][21][22]. Previous research from our group has identified the synergistic interactions between various peptides, CPPs, and established chemotherapeutic agents such as paclitaxel (PTX), 5-fluorouracil (5-FU), and clotrimazole (CLZ) by enhancing the delivery of chemotherapeutic agents to different cancer cells [23]. In addition, a different study explored the potent anticancer properties of CPP2-thiazole conjugates.…”