Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent

Abstract

The aldehyde dehydrogenases (ALDH) are a major family of detoxifying enzymes that contribute to cancer progression and therapy resistance. ALDH overexpression is associated with a poor prognosis in many cancer types. The use of multi-ALDH isoform or isoform-specific ALDH inhibitors as anticancer agents is currently hindered by the lack of viable candidates. Most multi-ALDH isoform inhibitors lack bioavailability and are nonspecific or toxic, whereas most isoform-specific inhibitors are not effective as monotherapy due to the overlapping functions of ALDH family members. The present study details the development of a novel, potent, multiisoform ALDH inhibitor, called KS100. The rationale for drug development was that inhibition of multiple ALDH isoforms might be more efficacious for cancer compared with isoform-specific inhibition. Enzymatic IC 50 s of KS100 were 207, 1,410, and 240 nmol/L toward ALDH1A1, 2, and 3A1, respectively. Toxicity of KS100 was mitigated by development of a nanoliposomal formulation, called NanoKS100. NanoKS100 had a loading efficiency of approximately 69% and was stable long-term. NanoKS100 was 5-fold more selective for killing melanoma cells compared with normal human fibroblasts. NanoKS100 administered intravenously at a submaximal dose (3-fold lower) was effective at inhibiting xenografted melanoma tumor growth by approximately 65% without organ-related toxicity. Mechanistically, inhibition by KS100 significantly reduced total cellular ALDH activity to increase reactive oxygen species generation, lipid peroxidation, and accumulation of toxic aldehydes leading to apoptosis and autophagy. Collectively, these data suggest the successful preclinical development of a nontoxic, bioavailable, nanoliposomal formulation containing a novel multi-ALDH isoform inhibitor effective in the treatment of cancer.

Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance

“…However, KS100 showed toxicity in vivo , leading to a significant weight loss after 14 days of treatment ( 91 ). In order to reduce/overcome toxicity, researchers have developed a nanoliposomal formulation of KS100, called NanoKS100 ( 92 ). Such PEGylated liposomal formulation not only improved bioavailability, reducing spleen and liver accumulation but also demonstrating to be effective and not toxic even at high doses ( 92 ).…”

“…In order to reduce/overcome toxicity, researchers have developed a nanoliposomal formulation of KS100, called NanoKS100 ( 92 ). Such PEGylated liposomal formulation not only improved bioavailability, reducing spleen and liver accumulation but also demonstrating to be effective and not toxic even at high doses ( 92 ). Despite promising results, broad-spectrum ALDH inhibitors might retain toxicity due to the wide distribution of ALDH enzymes also in normal/healthy tissues ( 1 ).…”

Salubrinal in Combination With 4E1RCat Synergistically Impairs Melanoma Development by Disrupting the Protein Synthetic Machinery

“…At the end of tumorigenicity assessment, blood was collected from each euthanized animal in a serum separator tube with lithium heparin (BD Microtainer) following cardiac puncture, and subjected to a routine available panel for assessing major organ-related toxicity (24,25,32,33). Levels of GLU (Glucose), BUN (Blood urea nitrogen), CREA (Creatinine), CAL (Calcium), TPR (Total Protein), ALB (Albumin), GLB (Globulin), ALT (Alanine aminotransferase), ALKP (Alkaline phosphatase), TBIL (Total bilirubin), and AMY (Amylase) were assessed as a part of the panel.…”

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

“…Most of these studies focus on developing direct depleting or inhibiting the CSC marker. For example, several inhibitors have been developed and/or tested to inhibit ALDH isoforms in cancer CSC studies a very active field [9,[98][99][100][101]. In addition, many of these studies have tested the effect of targeting CSC only (reviews [31,[54][55][56][57] and references herein).…”