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THE TRIFECTA: A NOVEL COMBINATORIAL THERAPY SPARES IMMUNE CELLS WHILE INDUCING IMMUNOGENIC CELL DEATH IN HUMAN MAMMARY ADENOCARCINOMA AND MOUSE MAMMARY CARCINOMA

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Date Issued:
2020
Abstract/Description:
According to U.S. Breast Cancer Statistics, about 1 in 8 U.S. women will develop invasive breast cancer during their lifetime. Chemotherapeutics that are used on patients currently often lead to tumor resistance, bone marrow suppression and cachexia. This study evaluated a novel combination of three non-mutagenic compounds for their effectiveness against mammary tumor cells, toxicity towards immune cells, ability to provoke the expression of immunogenic cell death (ICD) markers, and killing in 3D tumor models. Methotrexate (MTX), 2-deoxyglucose (2DG), and wogonin (WGN) were combined at doses well below their EC50 values yet effectively killed human and mouse breast cancer cells. The combination inhibited cancer cell colony formation and induced a high degree of cell death in multiple malignant tumor cell lines. Importantly, the combination did not significantly inhibit the viability of peripheral-blood mononuclear cells (PBMCs), even when employed at 3X the concentration that killed cancer cells. In marked contrast, low-dose doxorubicin, a common therapeutic for breast cancers, significantly decreased PBMC viability and increased the percentage of cell death. Our novel combinatorial therapy (Trifecta) elicited the significant expression of three ICD hallmarks: calreticulin surface expression, ATP secretion, and HMGB-1 release. In all cases, Trifecta elicited an equal or greater degree of ICD-marker expression compared to doxorubicin, a known inducer of ICD. We show significant efficacy of Trifecta against human and mouse mammary 3D tumor models grown in Matrigel® ECM-complex containing culture medium, and reaffirm the marked resistance of tumorspheres towards the conventional chemotherapeutic doxorubicin. The effectiveness of Trifecta in an acceptable surrogate model for mouse studies bodes well for translation of our findings to the clinic. In conclusion, Trifecta has proven highly effective against tumor cells grown either as monolayers or tumorspheres, without significant cytotoxic effects towards proliferating immune cells. Furthermore, treatment with this combination elicits ICD, which has the potential to prime an adaptive immune response against tumor cells and prevent future relapse. The drugs chosen for our combination target metabolic pathways that cancer cells are heavily dependent upon and do not interact with or induce mutations in DNA. These properties place Trifecta at the forefront of developing anticancer therapies.
Title: THE TRIFECTA: A NOVEL COMBINATORIAL THERAPY SPARES IMMUNE CELLS WHILE INDUCING IMMUNOGENIC CELL DEATH IN HUMAN MAMMARY ADENOCARCINOMA AND MOUSE MAMMARY CARCINOMA.
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Name(s): Motii, Youssef, author
Hartmann, James X. , Thesis advisor
Florida Atlantic University, Degree grantor
Department of Biological Sciences
Charles E. Schmidt College of Science
Type of Resource: text
Genre: Electronic Thesis Or Dissertation
Date Created: 2020
Date Issued: 2020
Publisher: Florida Atlantic University
Place of Publication: Boca Raton, Fla.
Physical Form: application/pdf
Extent: 202 p.
Language(s): English
Abstract/Description: According to U.S. Breast Cancer Statistics, about 1 in 8 U.S. women will develop invasive breast cancer during their lifetime. Chemotherapeutics that are used on patients currently often lead to tumor resistance, bone marrow suppression and cachexia. This study evaluated a novel combination of three non-mutagenic compounds for their effectiveness against mammary tumor cells, toxicity towards immune cells, ability to provoke the expression of immunogenic cell death (ICD) markers, and killing in 3D tumor models. Methotrexate (MTX), 2-deoxyglucose (2DG), and wogonin (WGN) were combined at doses well below their EC50 values yet effectively killed human and mouse breast cancer cells. The combination inhibited cancer cell colony formation and induced a high degree of cell death in multiple malignant tumor cell lines. Importantly, the combination did not significantly inhibit the viability of peripheral-blood mononuclear cells (PBMCs), even when employed at 3X the concentration that killed cancer cells. In marked contrast, low-dose doxorubicin, a common therapeutic for breast cancers, significantly decreased PBMC viability and increased the percentage of cell death. Our novel combinatorial therapy (Trifecta) elicited the significant expression of three ICD hallmarks: calreticulin surface expression, ATP secretion, and HMGB-1 release. In all cases, Trifecta elicited an equal or greater degree of ICD-marker expression compared to doxorubicin, a known inducer of ICD. We show significant efficacy of Trifecta against human and mouse mammary 3D tumor models grown in Matrigel® ECM-complex containing culture medium, and reaffirm the marked resistance of tumorspheres towards the conventional chemotherapeutic doxorubicin. The effectiveness of Trifecta in an acceptable surrogate model for mouse studies bodes well for translation of our findings to the clinic. In conclusion, Trifecta has proven highly effective against tumor cells grown either as monolayers or tumorspheres, without significant cytotoxic effects towards proliferating immune cells. Furthermore, treatment with this combination elicits ICD, which has the potential to prime an adaptive immune response against tumor cells and prevent future relapse. The drugs chosen for our combination target metabolic pathways that cancer cells are heavily dependent upon and do not interact with or induce mutations in DNA. These properties place Trifecta at the forefront of developing anticancer therapies.
Identifier: FA00013606 (IID)
Degree granted: Dissertation (Ph.D.)--Florida Atlantic University, 2020.
Collection: FAU Electronic Theses and Dissertations Collection
Note(s): Includes bibliography.
Subject(s): Cancer--Treatment
Breast--Cancer
Methotrexate
Deoxyglucose
wogonin
Held by: Florida Atlantic University Libraries
Sublocation: Digital Library
Persistent Link to This Record: http://purl.flvc.org/fau/fd/FA00013606
Use and Reproduction: Copyright © is held by the author with permission granted to Florida Atlantic University to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Use and Reproduction: http://rightsstatements.org/vocab/InC/1.0/
Host Institution: FAU
Is Part of Series: Florida Atlantic University Digital Library Collections.