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

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...

Full description

Bibliographic Details
Main Authors: Nuno Vale, Mariana Pereira, Joana Santos, Catarina Moura, Lara Marques, Diana Duarte
Format: Article
Language:English
Published: MDPI AG 2022-12-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/24/1/69
_version_ 1797625723535491072
author Nuno Vale
Mariana Pereira
Joana Santos
Catarina Moura
Lara Marques
Diana Duarte
author_facet Nuno Vale
Mariana Pereira
Joana Santos
Catarina Moura
Lara Marques
Diana Duarte
author_sort Nuno Vale
collection DOAJ
description 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 T<sub>max</sub>, 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.
first_indexed 2024-03-11T10:00:21Z
format Article
id doaj.art-e8679ae0f8ab41ea840e7afadde1a7ef
institution Directory Open Access Journal
issn 1661-6596
1422-0067
language English
last_indexed 2024-03-11T10:00:21Z
publishDate 2022-12-01
publisher MDPI AG
record_format Article
series International Journal of Molecular Sciences
spelling doaj.art-e8679ae0f8ab41ea840e7afadde1a7ef2023-11-16T15:28:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-012416910.3390/ijms24010069Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico ApproachesNuno Vale0Mariana Pereira1Joana Santos2Catarina Moura3Lara Marques4Diana Duarte5OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalOncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalOncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalOncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalOncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalOncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalChemotherapy 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 T<sub>max</sub>, 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.https://www.mdpi.com/1422-0067/24/1/69drug combinationcell-penetrating peptidescancer therapyin silicodrug synergism
spellingShingle Nuno Vale
Mariana Pereira
Joana Santos
Catarina Moura
Lara Marques
Diana Duarte
Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches
International Journal of Molecular Sciences
drug combination
cell-penetrating peptides
cancer therapy
in silico
drug synergism
title Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches
title_full Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches
title_fullStr Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches
title_full_unstemmed Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches
title_short Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches
title_sort prediction of drug synergism between peptides and antineoplastic drugs paclitaxel 5 fluorouracil and doxorubicin using in silico approaches
topic drug combination
cell-penetrating peptides
cancer therapy
in silico
drug synergism
url https://www.mdpi.com/1422-0067/24/1/69
work_keys_str_mv AT nunovale predictionofdrugsynergismbetweenpeptidesandantineoplasticdrugspaclitaxel5fluorouracilanddoxorubicinusinginsilicoapproaches
AT marianapereira predictionofdrugsynergismbetweenpeptidesandantineoplasticdrugspaclitaxel5fluorouracilanddoxorubicinusinginsilicoapproaches
AT joanasantos predictionofdrugsynergismbetweenpeptidesandantineoplasticdrugspaclitaxel5fluorouracilanddoxorubicinusinginsilicoapproaches
AT catarinamoura predictionofdrugsynergismbetweenpeptidesandantineoplasticdrugspaclitaxel5fluorouracilanddoxorubicinusinginsilicoapproaches
AT laramarques predictionofdrugsynergismbetweenpeptidesandantineoplasticdrugspaclitaxel5fluorouracilanddoxorubicinusinginsilicoapproaches
AT dianaduarte predictionofdrugsynergismbetweenpeptidesandantineoplasticdrugspaclitaxel5fluorouracilanddoxorubicinusinginsilicoapproaches