The Multifaceted Role of Aldehyde Dehydrogenases in Prostate Cancer Stem Cells

Püschel, Jakob; Dubrovska, Anna; Gorodetska, Ielizaveta

doi:10.3390/cancers13184703

Cited by 21 publications

(22 citation statements)

References 221 publications

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“…High expression of ALDH3A2 in the tumor tissue has been shown to be associated with prolonged overall survival in patients with gastric cancer and clear cell renal cell carcinoma ( 35 , 36 ). In prostate cancer, the expression of ALDH3A2 was decreased in the primary cancer tissue compared to the healthy prostate tissue but increased in response to anticancer treatments ( 37 ). Similarly, the expression of ALDH3A2 was downregulated in gastric cancer tissue compared to normal tissue ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Markers Associated With Tumor Recurrence in Patients With Breast Cancer Achieving a Pathologic Complete Response After Neoadjuvant Chemotherapy

Xie¹,

Wang²,

Chen³

et al. 2022

Front. Oncol.

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BackgroundPatients who achieve a tumor pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have better outcomes than patients with residual tumor. However, tumors still recur in the pCR patients. Therefore, we aim to explore factors associated with tumor recurrence in this patient population.MethodsA total of 1,913 patients diagnosed with breast cancer between 1995 and 2020 and received NAC were included in this analysis. Clinicopathological data of the patients were retrospectively collected. We used Cox regression analysis to assess the associations of clinicopathological factors with patients’ outcome. Proteomic study of tumors was applied to identify differentially expressed proteins (DEPs) between tumors from the pCR patients with tumor recurrence and tumors from those without tumor recurrence. PPI network analysis of the corresponding genes of DEPs was used to identify the hub genes. The prognostic value of the corresponding genes of DEPs was evaluated using two online databases, Kaplan-Meier Plotter and bc-GenExMiner. The genes that were significantly associated with patients’ survival in both databases, as well as being identified as hub genes, were considered as potential prognostic markers for pCR patients. Publicly available data from Gene Expression Omnibus (GEO) was used to verify the prognostic value of the identified marker.ResultsAmong the 1,913 included patients, 420 had tumor pCR. The median follow-up for the pCR patients was 32.6 months (IQR, 16.3-55.5). Overall estimated 5-year risk of tumor recurrence for the pCR patients was 11%. Multivariable analysis showed that a higher pre-NAC clinical T stage and N stage were independent predictors for increased risk of tumor recurrence (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.01-6.51, P=0.047 for clinical T stage and HR 3.48, 95%CI 1.37-8.83, P=0.009 for clinical N stage). NAC regimens, the type of breast and axillary surgery, and adjuvant chemotherapy were not associated with tumor recurrence. Finally, aldehyde dehydrogenase (ALDH) 3A2 was identified by the proteomic study and was verified as a potential predictor for tumor recurrence in the pCR patients (with a median follow up of 3.78 years for dataset GSE32603 and 2.74 years for dataset GSE25066 from GEO, tumor recurrence rate: low versus high expression, 20.7% versus 4.5% [data from GSE32603]; 10.9% versus 0% [data from GSE25066]).ConclusionsClinical T stage, clinical N stage and tumor expression of ALDH3A2 were potential markers for predicting tumor recurrence in the pCR patients after NAC.

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Section: Discussionmentioning

confidence: 99%

Markers Associated With Tumor Recurrence in Patients With Breast Cancer Achieving a Pathologic Complete Response After Neoadjuvant Chemotherapy

Xie¹,

Wang²,

Chen³

et al. 2022

Front. Oncol.

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“…It inhibits aldehyde dehydrogenase (ALDH), resulting in unpleasant accumulation of acetaldehyde if ethanol is consumed. ALDH is a central marker for stemness in both cancer cells and normal cells [143][144][145][146][147][148][149][150]. ALDH might be more properly termed a mediator of stem attributes.…”

Section: Disulfirammentioning

confidence: 99%

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

Kast¹,

Alfieri

Assi

et al. 2022

Cancers

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In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells’ growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass—by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs—celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan—to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of—not a replacement for—previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.

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“…It has been shown that ALDH high CD44 + PCa cells and the corresponding ALDH low CD44 − PCa cells manifest as PCSCs and non-PCSCs (20). A recent review by Dr. Jakob Püschel et al summarized the roles of different members in ALDH superfamily in PCSCs detailly (18). Among them, ALDH1A1 and ALDH3A1 are the most reported because they play a critical role in maintaining PCSC stemness (18,21,22).…”

Section: Introductionmentioning

confidence: 99%

“…A recent review by Dr. Jakob Püschel et al summarized the roles of different members in ALDH superfamily in PCSCs detailly (18). Among them, ALDH1A1 and ALDH3A1 are the most reported because they play a critical role in maintaining PCSC stemness (18,21,22). On the other hand, Dr. Saketh S. Dinavahi et al give us a detailed review of the latest progress on ALDH inhibitors in cancer therapy (23).…”

Section: Introductionmentioning

confidence: 99%

“…These prostate cancer stem cells (PCSCs) are responsible for PCa initiation, progression, therapy resistance, and metastasis ( 11 – 16 ). In addition, PCSCs have the characteristics of self-renewal and resistance to radiation or chemotherapy ( 13 , 14 , 16 , 17 ), and thus are effective targets for PCa treatment potentially ( 11 , 16 , 18 ). For instance, retinoic acid was used in clinical trials to drive the differentiation of PCSCs 80 .…”

Section: Introductionmentioning

confidence: 99%

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Targeting aldehyde dehydrogenase for prostate cancer therapies

Zhao

et al. 2022

Front. Oncol.

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Prostate cancer (PCa) is the most common cancer in men in the United States. About 10 – 20% of PCa progress to castration-resistant PCa (CRPC), which is accompanied by metastasis and therapeutic resistance. Aldehyde dehydrogenase (ALDH) is famous as a marker of cancer stem-like cells in different cancer types, including PCa. Generally, ALDHs catalyze aldehyde oxidation into less toxic carboxylic acids and give cancers a survival advantage by reducing oxidative stress caused by aldehyde accumulation. In PCa, the expression of ALDHs is associated with a higher tumor stage and more lymph node metastasis. Functionally, increased ALDH activity makes PCa cells gain more capabilities in self-renewal and metastasis and reduces the sensitivity to castration and radiotherapy. Therefore, it is promising to target ALDH or ALDHhigh cells to eradicate PCa. However, challenges remain in moving the ALDH inhibitors to PCa therapy, potentially due to the toxicity of pan-ALDH inhibitors, the redundancy of ALDH isoforms, and the lack of explicit understanding of the metabolic signaling transduction details. For targeting PCa stem-like cells (PCSCs), different regulators have been revealed in ALDHhigh cells to control cell proliferation and tumorigenicity. ALDH rewires essential signaling transduction in PCa cells. It has been shown that ALDHs produce retinoic acid (RA), bind with androgen, and modulate diverse signaling. This review summarizes and discusses the pathways directly modulated by ALDHs, the crucial regulators that control the activities of ALDHhigh PCSCs, and the recent progress of ALDH targeted therapies in PCa. These efforts will provide insight into improving ALDH-targeted treatment.

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The Multifaceted Role of Aldehyde Dehydrogenases in Prostate Cancer Stem Cells

Cited by 21 publications

References 221 publications

Markers Associated With Tumor Recurrence in Patients With Breast Cancer Achieving a Pathologic Complete Response After Neoadjuvant Chemotherapy

Markers Associated With Tumor Recurrence in Patients With Breast Cancer Achieving a Pathologic Complete Response After Neoadjuvant Chemotherapy

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

Targeting aldehyde dehydrogenase for prostate cancer therapies

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