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New Insights into the Structural Requirements of Isatin-Derived Pro-Apoptotic Agents against Acute Myeloid Leukemia.

ABSTRACT: Searching for bioactive compounds within the huge chemical space is like trying to find a needle in a haystack. Isatin is a unique natural compound which is endowed with different bio-pertinent activities, especially in cancer therapy. Herein, we envisaged that adopting a hybrid strategy of isatin and α,β-unsaturated ketone would afford new chemical entities with strong chemotherapeutic potential. Of interest, compounds 5b and 5g demonstrated significant antiproliferative activities against different cancer genotypes according to NCI-60 screening. Concomitantly, their IC₅₀ against HL-60 cells were 0.38 ± 0.08 and 0.57 ± 0.05 µM, respectively, demonstrating remarkable apoptosis and moderate cell cycle arrest at G1 phase. Intriguingly, an impressive safety profile for 5b was reflected by a 37.2 times selectivity against HL-60 over PBMC from a healthy donor. This provoked us to further explore their mechanism of action by in vitro and in silico tools. Conclusively, 5b and 5g stand out as strong chemotherapeutic agents that hold clinical promise against acute myeloid leukemia.

SUBMITTER: Hamdy AK

PROVIDER: S-EPMC9784816 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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New Insights into the Structural Requirements of Isatin-Derived Pro-Apoptotic Agents against Acute Myeloid Leukemia.

Hamdy Ahmed K AK Sakamoto Takashi T Toma Tsugumasa T Sakamoto Masaharu M Abourehab Mohammed A S MAS Otsuka Masami M Fujita Mikako M Tateishi Hiroshi H Radwan Mohamed O MO

Pharmaceuticals (Basel, Switzerland) 20221217 12

Searching for bioactive compounds within the huge chemical space is like trying to find a needle in a haystack. Isatin is a unique natural compound which is endowed with different bio-pertinent activities, especially in cancer therapy. Herein, we envisaged that adopting a hybrid strategy of isatin and α,β-unsaturated ketone would afford new chemical entities with strong chemotherapeutic potential. Of interest, compounds <b>5b</b> and <b>5g</b> demonstrated significant antiproliferative activitie ...[more]

PMID: 36559030

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Project description:Venetoclax is used for the priority treatment of elderly patients with acute myeloid leukemia (AML). Resistance or intolerance to venetoclax offsets its clinical benefits in some patients. Combination strategies with other drugs are promising alternatives to overcome the current complications associated with venetoclax use. Hymeglusin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), regulates the mevalonate pathway, which is vital for AML growth and chemosensitivity. The effects of the combination of venetoclax and hymeglusin on AML were explored in this study. The correlations between HMGCS1 and apoptosis-related genes were analyzed using the Gene Expression Profiling Interactive Analysis 2 and The Cancer Genome Atlas databases. Apoptosis and cell viability were detected in HL-60 and KG-1 cells after treatment with gradient concentrations of venetoclax or hymeglusin. The transcriptomic profiles of HL-60 and KG-1 cells were compared via RNA-Seq analysis. The effects of venetoclax and hymeglusin on apoptosis were validated in primary cells. The results showed that HMGCS1 expression was closely associated with apoptosis-related genes based on the data from large clinical databases. B cell lymphoma (BCL)-2 expression was elevated in AML and negatively associated with overall survival. Hymeglusin decreased BCL2 expression levels in HL-60 and KG-1 cells. Venetoclax and hymeglusin inhibited cell viability in both cell lines, but induced apoptosis in HL-60 cells. This discrepancy in sensitivity to hymeglusin may be attributed to the positive increase in the expression levels of HMGCS1 and multiple upregulated pro-leukemia genes in KG-1 cells. Combination treatment with venetoclax and hymeglusin significantly increased the apoptotic rates compared to single-agent treatment in both AML cell lines and primary AML cells. Furthermore, the combination strategy did not result in remarkably enhanced toxicity in normal mononuclear cells. Collectively, hymeglusin enhanced the effects of venetoclax on apoptosis. This combination strategy showed enhanced antileukemic activity with acceptable toxicity in AML.

Project description:The voltage-dependent anion channel 1 (VDAC1), localized in the outer mitochondrial membrane, mediates metabolic cross-talk between the mitochondrion and the cytoplasm and thus serves a fundamental role in cell energy metabolism. VDAC1 also plays a key role in mitochondria-mediated apoptosis, interacting with anti-apoptotic proteins. Resistance of cancer cells to apoptosis involves quenching the mitochondrial apoptotic pathway by over-expression of anti-apoptotic/pro-survival hexokinase (HK) and Bcl-2 family proteins, proteins that mediate their anti-apoptotic activities via interaction with VDAC1. Using specifically designed VDAC1-based cell-penetrating peptides, we targeted these anti-apoptotic proteins to prevent their pro-survival/anti-apoptotic activities. Anti-apoptotic proteins are expressed at high levels in B-cell chronic lymphocytic leukemia (CLL), an incurable disease requiring innovative new approaches to improve therapeutic outcome. CLL is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Specifically, we demonstrate that the VDAC1-based peptides (Antp-LP4 and N-Terminal-Antp) selectively kill peripheral blood mononuclear cells (PBMCs) obtained from CLL patients, yet spare those obtained from healthy donors. The cell death induction competence of the peptides was well correlated with the amount of double positive CD19/CD5 cancerous CLL PBMCs, further illustrating their selectivity toward cancer cells. Moreover, these VDAC1-based peptides induced apoptosis by activating the mitochondria-mediated pathway, reflected in membrane blebbing, condensation of nuclei, DNA fragmentation, release of mitochondrial cytochrome c, loss of mitochondrial membrane potential, decreased cellular ATP levels and detachment of HK, all leading to apoptotic cell death. Thus, the mode of action of the peptides involves decreasing energy production and inducing apoptosis. Over 27 versions of cell-penetrating VDAC1-based peptides were designed and screened to identify the most stable, short and apoptosis-inducing peptides toward CLL-derived lymphocytes. In this manner, three optimized peptides suitable for in vivo studies were identified. This study thus reveals the potential of VDAC1-based peptides as an innovative and effective anti-CLL therapy.

Dataset Information

New Insights into the Structural Requirements of Isatin-Derived Pro-Apoptotic Agents against Acute Myeloid Leukemia.

Publications

New Insights into the Structural Requirements of Isatin-Derived Pro-Apoptotic Agents against Acute Myeloid Leukemia.

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