Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies
Abstract
:1. Introduction
2. Gynecologic Malignancies: An Overview
2.1. Cervical Cancer
2.2. Uterine Cancer
2.3. Ovarian Cancer
2.4. Vulvar Cancer
2.5. Vaginal Cancer
3. ALDH in Gynecologic Cancers
3.1. ALDH and Cervical Cancer
3.2. ALDH and Uterine Cancer
3.3. ALDH and Ovarian Cancer
3.4. ALDH and Vulvar Cancer
4. ALDH-Targeted Therapies for Gynecologic Cancers
4.1. Agents Directly Targeting ALDH
4.1.1. Disulfiram
4.1.2. 4-Diethylaminobenzaldehyde
4.1.3. All-Trans Retinoic Acid (ATRA)
4.1.4. NCT-501, NCT-505, and NCT-506
4.1.5. CM037
4.1.6. 13g, 13h
4.1.7. 673A
4.2. Agents Indirectly Targeting ALDH
4.2.1. JQ1
4.2.2. Anti-EMP2 IgG1
4.2.3. Peptide Nucleic Acid
4.2.4. miR-23b
4.3. Combination Therapies using ALDH Inhibitors
5. Challenges and Future Directions
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
CSC | cancer stem cells |
ALDH | aldehyde dehydrogenases |
RA | retinoic acid |
ROS | reactive oxygen species |
ABC | adenosine triphosphate binding cassette |
ATM | ataxia-telangiectasia-mutated |
ATR | ataxia telangiectasia and rad3-related |
Chk1 | checkpoint kinase 1 |
PARP1 | poly-ADP-ribose polymerase 1 |
BAAA | Bodipy-aminoacetaldehyde |
BAA | Bodipy-aminoacetate |
CC | Cervical cancer |
SCC | squamous cell carcinoma |
IARC | International Agency for Research on Cancer |
EC | endometrial cancer |
OC | Ovarian cancer |
HGSOC | high grade serous ovarian cancer |
CIN | cervical intraepithelial neoplasia |
Oct4 | octamer-binding transcription factor 4 |
Sox2 | sex determining region Y-box 2 |
Twist 1 | Twist-related protein 1 |
Hey 1 | Hes related family BHLH transcription factor with YRPW motif 1 |
Klf4 | Kruppel like factor 4 |
HOXA10 | Homeobox A10 |
HOXA11 | Homeobox A11 |
siRNA | small interfering ribonucleic acid |
DSF | Disulfiram |
DEAB | 4-Diethylaminobenzaldehyde |
P-gp | P-glycoprotein |
BRCP | breast cancer resistance protein |
HTS | high-throughput screening |
ATRA | All-trans retinoic acid |
Nrf-2 | nuclear factor erythroid-2-related factor 2 |
i.p. | intraperitoneal administration |
DDB2 | DNA damage-binding protein |
CETSA | cellular thermal shift assay |
BRD4 | Bromodomain-containing protein 4 |
EMP2 | epithelial membrane protein-2 |
lncRNA | long non-coding RNA |
HOTAIR | HOX antisense intergenic RNA |
PNA | peptide nucleic acid |
miR | micro-RNAs |
UTR | untranslated region |
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Gynecologic Malignancy | Cancer Stem Cells | References |
---|---|---|
Cervical cancer | Reported in literature | [8,9,10] |
Uterine cancer | Reported in literature | [11,12,13,14] |
Ovarian cancer | Reported in literature | [15,16,17,18,19] |
Vulvar cancer | Reported in literature | [20] |
Vaginal cancer | No published reports | - |
Compound | ALDH Isoform Specificity | Gynecologic Malignancy | Preclinical Studies | References |
---|---|---|---|---|
Disulfiram | ALDH2, ALDH1 | Ovarian Cervical | Orally bioavailable. Limited in vivo efficacy in ovarian cancer mouse model | [100,101,102,103] |
DEAB | ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH2, ALDH3A1, ALDH5A1 | Ovarian Endometrial | No in vivo studies found | [80,82,104,105] |
ATRA | ALDH1, ALDH1A1, ALDH1A3 | Ovarian Cervical | Reduced in vivo tumorigenesis in ovarian cancer | [106,107,108] |
NCT 501 | ALDH1A1 | Ovarian Endometrial | Halted tumor re-growth in orthotropic ovarian cancer xenograft model | [85,109,110] |
NCT-505 NCT-506 | ALDH1A1 | Ovarian | Orally bioavailable No weight loss or mortality in pilot toxicity studies | [108] |
CM037 (A37) | ALDH1A1 | Ovarian Endometrial | Ineffective in vivo likely due to low aqueous solubility Non-toxic to mice at 20 mg/kg | [84,110,111] |
13g 13h | ALDH1A | Ovarian | Showed excellent in vivo efficacy on i.p. administration in OC mouse model | [112] |
673A | ALDH1A1, ALDH1A2, ALDH1A3 | Ovarian | Highly synergistic with chemotherapy in reducing tumor initiation and increasing tumor eradication | [80] |
Therapeutic Agent | Target | Gynecologic Malignancy | In Vivo Studies Reported | References |
---|---|---|---|---|
JQ1 | BRD4 | Ovarian cancer | JQ1 in combination with cisplatin improved survival of OC bearing mice in an orthotopic model | [140] |
Anti-EMP2 IgG1 | EMP2 | Endometrial cancer | Reduces CSCs and secondary tumor formation in mice | [141] |
PNA | HOTAIR | Ovarian cancer | Reduced tumor formation and improved survival in mice with platinum-resistant ovarian tumor xenografts | [142] |
miR-23b | 3’UTR of ALDH1A1 | Cervical cancer | No in vivo studies reported | [143] |
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Muralikrishnan, V.; Hurley, T.D.; Nephew, K.P. Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies. Cancers 2020, 12, 961. https://doi.org/10.3390/cancers12040961
Muralikrishnan V, Hurley TD, Nephew KP. Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies. Cancers. 2020; 12(4):961. https://doi.org/10.3390/cancers12040961
Chicago/Turabian StyleMuralikrishnan, Vaishnavi, Thomas D. Hurley, and Kenneth P. Nephew. 2020. "Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies" Cancers 12, no. 4: 961. https://doi.org/10.3390/cancers12040961