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Targeting ALDH1 to decrease tumorigenicity, growth and metastasis of human melanoma
Lili Yue1, Zhi-Ming Huang, Stephen Fong
1Departments of aDermatology bSurgery, University California at San Francisco cDepartment of Dermatology, Veterans Affairs Medical Center, San Francisco dDepartment of Surgery, University California at Irvine, Irvine, California, USA.
Abstract:
Cells with aldehyde dehydrogenase activity (ALDH+) are the most tumorigenic cells in many cancers, including melanoma, making ALDH a candidate therapeutic target. We examined the effects of chemical inhibition of ALDH1 on the response of human melanoma xenografts to chemotherapy and the effects of ALDH1A1 RNA silencing on melanoma growth and metastasis. Addition of ALDH1 inhibitors (e.g. diethylaminobenzaldehyde) to dacarbazine chemotherapy, not only reduced tumor growth in vivo, but also resulted in a significant decrease in the number of residual cells capable of tumorigenesis. shRNA depletion of ALDH1A1 in melanoma cells resulted not only in a significant delay in appearance of xenograft melanomas and reduction in growth, but also significantly decreased the number of metastases and metastatic burden after lateral tail vein injections in mice. In summary, ALDH1 inhibition in combinatorial therapy with dacarbazine reduced the number of residual tumorigenic cells post-therapy and ALDH1A1 depletion had marked inhibitory effects on both melanoma growth and metastasis. These findings suggest that ALDH1 inhibition may not only be able to provide a therapeutic advantage in melanoma treatment, but may also prevent rapid relapse after therapy, as residual tumorigenic cells are fewer and metastatic ability is diminished.
Insights
Aldehyde dehydrogenase 1 (ALDH1) inhibition targets tumorigenic melanoma cells. Combining ALDH1 inhibitors with chemotherapy reduced tumor growth and metastasis, suggesting a new therapeutic strategy for melanoma.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Aldehyde dehydrogenase (ALDH+) cells are highly tumorigenic in melanoma.
- ALDH represents a potential therapeutic target for melanoma treatment.
- Understanding ALDH's role is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the therapeutic potential of ALDH1 inhibition in melanoma.
- To evaluate the combined effects of ALDH1 inhibitors and chemotherapy.
- To assess the impact of ALDH1A1 RNA silencing on melanoma growth and metastasis.
Main Methods:
- Utilized chemical ALDH1 inhibitors (e.g., diethylaminobenzaldehyde) in combination with dacarbazine chemotherapy.
- Employed shRNA to deplete ALDH1A1 in melanoma cells.
- Assessed tumor growth, residual tumorigenic cells, and metastasis in mouse xenograft models.
Main Results:
- Combined ALDH1 inhibition and dacarbazine chemotherapy reduced melanoma tumor growth and the number of residual tumorigenic cells.
- ALDH1A1 depletion significantly delayed melanoma xenograft appearance and reduced tumor growth.
- ALDH1A1 silencing markedly decreased melanoma metastasis and overall metastatic burden.
Conclusions:
- ALDH1 inhibition shows promise as a therapeutic strategy for melanoma, potentially enhancing chemotherapy efficacy.
- Targeting ALDH1 may reduce residual cancer cells, preventing tumor relapse.
- ALDH1A1 depletion effectively inhibits melanoma growth and metastasis, indicating its critical role in disease progression.
