Design principles of drug combinations for chemotherapy

Wu, Debra; Pusuluri, Anusha; Vogus, Douglas R.; Krishnan, Vinu; Shields, C. Wyatt; Kim, Jayoung; Razmi, Amaya; Mitragotri, Samir

doi:10.1016/j.jconrel.2020.04.018

Cited by 39 publications

(27 citation statements)

References 56 publications

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“…Another important mechanism of 5-FU-induced cytotoxicity is its misincorporation into RNA and DNA in the place of uracil or thymine that consequently activates DNA repair and finally double-strand break (DSB) induction and DNA damage [ 7 ]. Due to its cytotoxicity [ 8 ] and resistance occurrence, 5-FU is one of the most commonly used TS-directed anticancer drugs applied in combination with other chemotherapy compounds for the treatment of various cancers, including breast cancer [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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“…The encapsulation efficiency of GEM and DOX remained similar to previously reported values. 19 The size and zeta potential of the formulations remained similar, showing that incorporation of a small amount of MPLA does not significantly change the liposome physical properties (Table 1).…”

Section: Liposome Fabricationmentioning

confidence: 88%

Gemcitabine and doxorubicin in immunostimulatory monophosphoryl lipid A liposomes for treating breast cancer

Zhao

Kim

et al. 2020

Bioengineering & Transla Med

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Cancer therapy is increasingly shifting toward targeting the tumor immune microenvironment and influencing populations of tumor infiltrating lymphocytes. Breast cancer presents a unique challenge as tumors of the triple-negative breast cancer subtype employ a multitude of immunosilencing mechanisms that promote immune evasion and rapid growth. Treatment of breast cancer with chemotherapeutics has been shown to induce underlying immunostimulatory responses that can be further amplified with the addition of immune-modulating agents. Here, we investigate the effects of combining doxorubicin (DOX) and gemcitabine (GEM), two commonly used chemotherapeutics, with monophosphoryl lipid A (MPLA), a clinically used TLR4 adjuvant derived from liposaccharides. MPLA was incorporated into the lipid bilayer of liposomes loaded with a 1:1 molar ratio of DOX and GEM to create an intravenously administered treatment. In vivo studies indicated excellent efficacy of both GEM-DOX liposomes and GEM-DOX-MPLA liposomes against 4T1 tumors. In vitro and in vivo results showed increased dendritic cell expression of CD86 in the presence of liposomes containing chemotherapeutics and MPLA. Despite this, a tumor rechallenge study indicated little effect on tumor growth upon rechallenge, indicating the lack of a long-term immune response. GEM/DOX/MPLA-L displayed remarkable control of the primary tumor growth and can be further explored for the treatment of triple-negative breast cancer with other forms of immunotherapy.

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“…Liposomal formulations have an additional effect on the drug's metabolism, decreasing its enzymatic degradation (Bulbake et al, 2017) The drug combination strategy goes through experimental steps in vivo and in vitro that are challenging because they include the need to optimize cytotoxicity, not only of the drug, but of the drug interactions, pharmacokinetics and antitumor activity. Studies carried out on the use of nanotechnology have achieved satisfactory results and it is expected that they will advance to the clinical phase, making it possible later on to introduce them into therapeutic practice and commercialization (Wu et al, 2020).…”

Section: Nanotechnology Platform For Drug Combinationmentioning

confidence: 99%

Drug combination and nanooncology for improvement in the treatment of breast cancer: a review

Faria

Souza

Pacheco

et al. 2021

RSD

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Optimizing drug combination treatment has been an area of interest for a while, from the beginning with the emergence of the POMP regime. The ability to improve drug combinations for cancer treatment comes up against the possibility of several limitations, such as the lack of specificity of the drugs, generating systemic toxic effects, and also the great possibility of generating tumor cells resistant to the drugs. The development of nanooncology offers advances in new alternatives for the treatment of cancer, especially breast cancer. The strategy of using drugs combined in a nanocarrier for the treatment of breast cancer has proven to be quite effective, taking into account that breast cancer has long shown a good response with therapeutic combinations. In this work, we present a review of some examples of nanoformulations developed with the combination of drugs doxorubicin and/or paclitaxel aimed for the treatment of breast cancer. Also the future perspectives of nanotechnology in the drug combination.

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Design principles of drug combinations for chemotherapy

Cited by 39 publications

References 56 publications

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Gemcitabine and doxorubicin in immunostimulatory monophosphoryl lipid A liposomes for treating breast cancer

Drug combination and nanooncology for improvement in the treatment of breast cancer: a review

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