TY - JOUR
T1 - Rational Drug Design of Targeted and Enzyme-Cleavable Vitamin E Analogs as a Neoadjuvant to Chemotherapy
T2 - In Vitro and In Vivo Evaluation on Reduction of the Cardiotoxicity Side Effect of Doxorubicin
AU - Pandurangi, Raghu S.
AU - Cseh, Orsolya
AU - Luchman, Hema Artee
AU - Ma, Cynthia Xiuguang
AU - Senadheera, Sanjeewa N.
AU - Forrest, Marcus Laird
N1 - Funding Information:
R.P. acknowledges the collaborative efforts from all authors. Special thanks to the animal facilities/personnel of John Hopkins University including Dr. Katherine Gabrielson. We also thank Dr. J. L. Vanderheyden, Industrial consultant for SEMCO, for his deep involvement in discussions and Dr. Bengt Bergstrom, MD, Ph.D., CEO of SEMCO, for his clinical perspectives. The work was carried out with funds through SEMCO internal funds and NIH SBIR grant R43CA214223. Funding organization did not play any roles in designing experiments, data collection, analysis, or any decision to publish the data. The rat in vivo data were collected at Johns Hopkins University under the guidance from Prof. Kathleen Gabrielson with the funding outsourced from the SBIR grant.
Funding Information:
The work was carried out with funds through SEMCO internal funds and NIH SBIR grant R43CA214223. Funding organization did not play any roles in designing experiments, data collection, analysis, or any decision to publish the data. The rat in vivo data were collected at Johns Hopkins University under the guidance from Prof. Kathleen Gabrielson with the funding outsourced from the SBIR grant.
Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/3/10
Y1 - 2023/3/10
N2 - Traditional drug design focuses on specific biological targets where specific receptors or biomarkers are overexpressed by cancer cells. Cancer cells circumvent the interventions by activating survival pathways and/or downregulating cell death pathways for their survival. A priori activation of apoptosis pathways of tumor (AAAPT) is a novel tumor-sensitizing technology that sensitizes tumor cells that are not responding well to the current treatments by targeting specific survival pathways involved in the desensitization of tumor cells and tries to revive them selectively in cancer cells, sparing normal cells. Several vitamin E derivatives (AMP-001, AMP-002, AMP-003, and AMP-004) were synthesized, characterized, and studied for their anti-tumorigenic properties and their synergistic potential with the standard chemotherapy doxorubicin in various cancer cells including brain cancer stem cells in vitro. Preliminary studies revealed that AAAPT drugs (a) reduced the invasive potential of brain tumor stem cells, (b) synergized with Federal Drug Application-approved doxorubicin, and (c) enhanced the therapeutic index of doxorubicin in the triple-negative breast cancer tumor rat model, preserving the ventricular function compared to cardiotoxic doxorubicin alone at therapeutic dose. The AAAPT approach has the advantage of inhibiting survival pathways and activating cell death pathways selectively in cancer cells by using targeting, linkers cleavable by tumor-specific Cathepsin B, and PEGylation technology to enhance the bioavailability. We propose AAAPT drugs as a neoadjuvant to chemotherapy and not as stand-alone therapy, which is shown to be effective in expanding the therapeutic index of doxorubicin and making it work at lower doses.
AB - Traditional drug design focuses on specific biological targets where specific receptors or biomarkers are overexpressed by cancer cells. Cancer cells circumvent the interventions by activating survival pathways and/or downregulating cell death pathways for their survival. A priori activation of apoptosis pathways of tumor (AAAPT) is a novel tumor-sensitizing technology that sensitizes tumor cells that are not responding well to the current treatments by targeting specific survival pathways involved in the desensitization of tumor cells and tries to revive them selectively in cancer cells, sparing normal cells. Several vitamin E derivatives (AMP-001, AMP-002, AMP-003, and AMP-004) were synthesized, characterized, and studied for their anti-tumorigenic properties and their synergistic potential with the standard chemotherapy doxorubicin in various cancer cells including brain cancer stem cells in vitro. Preliminary studies revealed that AAAPT drugs (a) reduced the invasive potential of brain tumor stem cells, (b) synergized with Federal Drug Application-approved doxorubicin, and (c) enhanced the therapeutic index of doxorubicin in the triple-negative breast cancer tumor rat model, preserving the ventricular function compared to cardiotoxic doxorubicin alone at therapeutic dose. The AAAPT approach has the advantage of inhibiting survival pathways and activating cell death pathways selectively in cancer cells by using targeting, linkers cleavable by tumor-specific Cathepsin B, and PEGylation technology to enhance the bioavailability. We propose AAAPT drugs as a neoadjuvant to chemotherapy and not as stand-alone therapy, which is shown to be effective in expanding the therapeutic index of doxorubicin and making it work at lower doses.
KW - IC50
KW - PEGylation
KW - US imaging
KW - brain tumor stem cells
KW - ejection fraction
KW - synergy
KW - triple-negative breast cancer
UR - http://www.scopus.com/inward/record.url?scp=85147802117&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.2c00091
DO - 10.1021/acsptsci.2c00091
M3 - Article
C2 - 36926453
AN - SCOPUS:85147802117
SN - 2575-9108
VL - 6
SP - 372
EP - 386
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 3
ER -