Targeting aldehyde dehydrogenase: a potential approach for cell labeling

Abstract

Introduction-To advance the science and clinical application of stem cell therapy, the availability of a highly sensitive, quantitative, and translational method for tracking stem cells would be invaluable. Because hematopoetic stem cells express high levels of the cytosolic enzyme aldehyde dehydrogenase-1A1 (ALDH1), we sought to develop an agent that is specific to ALDH1 and thus to cells expressing the enzyme. Such an agent might be also helpful in identifying tumors that are resistant to cyclophosphomide chemotherapy because ALDH1 is known to be responsible for this resistance. Results-The average radiochemical yields for the synthesis [ 125 I]FMIC and [ 125 I]DEIBA were 70 ± 5% and 47 ± 14%, respectively. ALDH1 converted both compounds to respective acids suggesting their suitability as ALDH1 imaging agents. Although ability of ALDH1 within the cells to oxidize one of these substrates was shown, specific uptake in ALDH-expressing tumor cells could not be demonstrated. Methods-WeConclusion-To pursue this approach for ALDH1 imaging, radiolabeled aldehydes need to be designed such that, in addition to being good substrates for ALDH1, the cognate products should be sufficiently polar so as to be retained within the cells.

Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors

“…In addition, attempts at in vivo stem cell labeling have employed ALDH radiolabeled substrates. However, the resultant charged compounds were not polar enough to be retained into the cells [ 59 ].…”

A red-shifted fluorescent substrate for aldehyde dehydrogenase

“…The degree of trapping is particularly challenging to control as those two compounds initially stained cells but failed to accumulate. Vaidyanathan et al reported two radiolabeled ALDH substrates that could be converted into the acid form by the purified enzyme 25 . Both substrates, however, failed to accumulate inside of cells with high ALDH activity when compared with the DEAB control.…”

Next generation of ALDH substrates and their potential to study maturational lineage biology in stem and progenitor cells

“…Since early detection of cancer is key for curative treatment, there is considerable interest in noninvasive and inexpensive cancer diagnosis. Targeting ALDH as a potential approach for cancer cell labeling might be an appropriate “tracer” for discerning drug-sensitive and drug-resistant phenotypes of cancers to evaluate the effectiveness of novel therapies ( 27 ). Ultimately, targeted killing of a cell, based upon its specialized metabolic state (here ALDH activity), may be useful for clinical application to preferentially target those rapidly proliferating cells for growth inhibition or death, as has been described in the case of threonine dehydrogenase in mouse embryonic stem cells ( 1 ).…”