Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines

Verma, Kshitij; Zang, Tianzhu; Gupta, Nehal; Penning, T.M.; Trippier, Paul C.

doi:10.1021/acsmedchemlett.6b00163

Cited by 40 publications

(55 citation statements)

References 34 publications

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“…Inhibitors of AKR1C3 from various structural classes [flavones (30), jasmonates (31), and NSAIDS (23, 33)] have previously been described. We adopted a cinnamic acid derivative "baccharin" and conducted structure-activity relationship (SAR) studies to identify lead AKR1C3 inhibitors (37,38). The cinnamic acid derivative KV-37 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1A) was chosen for further studies as it demonstrated potent AKR1C3 inhibition (IC 50 ¼ 66 nmol/L) and selectivity (109-fold over AKR1C2; ref. 38). In order to delineate the preliminary mechanism of action, we tested its mode of AKR1C3 inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…For pretreatment experiments, cells were treated with KV-37 for 24 hours followed by the addition of ENZ and incubated for a further 72 hours. Cell viability was determined by the MTS tetrazolium dye assay as described previously (38). No intrinsic absorbance was noted with either KV-37 or ENZ in the MTS assay.…”

Section: Cell Viability Assaysmentioning

confidence: 99%

“…[36][37][38], in androgen-sensitive prostate cancer cell lines and a xenograft model. We have previously reported AKR1C3 inhibitors that act synergistically with etoposide and daunorubicin as chemotherapeutic agents in a panel of leukemia cell lines (38). The AKR1C3 inhibitor KV-37 exerts high synergistic drug interaction in combination with ENZ, which is superior to that seen with INDO.…”

Section: Introductionmentioning

confidence: 99%

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AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

Verma

Gupta

Zang

et al. 2018

Molecular Cancer Therapeutics

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Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17 β-hydroxysteroid dehydrogenase, is responsible for intratumoral androgen biosynthesis, contributing to the development of castration-resistant prostate cancer (CRPC) and eventual chemotherapeutic failure. Significant upregulation of AKR1C3 is observed in CRPC patient samples and derived CRPC cell lines. As AKR1C3 is a downstream steroidogenic enzyme synthesizing intratumoral testosterone (T) and 5α-dihydrotestosterone (DHT), the enzyme represents a promising therapeutic target to manage CRPC and combat the emergence of resistance to clinically employed androgen deprivation therapy. Herein, we demonstrate the antineoplastic activity of a potent, isoform-selective and hydrolytically stable AKR1C3 inhibitor ()-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl)acrylic acid (), which reduces prostate cancer cell growth and and sensitizes CRPC cell lines (22Rv1 and LNCaP1C3) toward the antitumor effects of enzalutamide. Crucially, does not induce toxicity in nonmalignant WPMY-1 prostate cells nor does it induce weight loss in mouse xenografts. Moreover, reduces androgen receptor (AR) transactivation and prostate-specific antigen expression levels in CRPC cell lines indicative of a therapeutic effect in prostate cancer. Combination studies of with enzalutamide reveal a very high degree of synergistic drug interaction that induces significant reduction in prostate cancer cell viability via apoptosis, resulting in>200-fold potentiation of enzalutamide action in drug-resistant 22Rv1 cells. These results demonstrate a promising therapeutic strategy for the treatment of drug-resistant CRPC that invariably develops in prostate cancer patients following initial treatment with AR antagonists such as enzalutamide. .

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Cell Viability Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

Verma

Gupta

Zang

et al. 2018

Molecular Cancer Therapeutics

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“…In pretreatment experiments, KV37 afforded six-fold potentiation of etoposide and ten-fold potentiation of daunorubicin. Low concentration treatment of KV37 resensitized daunorubicin-resistant AML cell lines to the cytotoxic action of the drug [20].…”

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confidence: 99%

Small Molecule Inhibitors for Acute Myeloid Leukemia: Where is the Field Heading?

Trippier

2017

Future Med. Chem.

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Acute myeloid leukemia (AML) is a hematologic neoplasm characterized by proliferation of poorly differentiated myeloid progenitor cells [1]. The neoplasm results from either de novo factors or as a side effect of chemotherapy for the treatment of other cancers; therapy-related AML [2,3]. The incidence rate among adults younger than 65 is 1.2%. However, the neoplasm is more prevalent in the elderly with an incidence of 17.6 per 100,000 for those older than 65, with a median age of onset of 67 [4]. A majority of patients relapse and die of the disease within 2 years of remission [5]. Survival rates in patients older than 65 at 5 years are just 6-12% [6]. AML accounts for 25% of acute leukemias in children, yet is responsible for >50% of leukemia-related deaths.Improvements in AML therapy have been limited and approximately, only 40-50% of adult patients with AML are cured [7]. Young (<1 year old) age [8] and older age are widely recognized risk factors for one of the major causes of therapeutic failure in AML; that patients are not able to tolerate the toxicity associated with the most intensive chemotherapeutic treatment regimes, resulting in an increased rate of early death. The second major cause of therapeutic failure is relapse due to therapeutic resistance [9], which is particularly significant in acute promyelocytic leukemia [10,11], a subtype of AML.The incidence and mortality rate, potential for resistance, and limited therapeutic options combine to make the discovery of alternative chemotherapeutics critical for patients, particular infants and those older than 65, diagnosed with AML. To date, the use of alternative chemotherapeutics in AML has been largely disappointing [4]. However, small molecule inhibitors of a number of recently identified protein targets offer new therapeutic options tailored to specific mutations or to counter resistance. In the rapidly growing field of precision (or genomic) medicine, the exact molecular aberrations present in individual patient samples can be determined and exploited for targeted therapy, resulting in greater therapeutic response [12]; an approach used to great effect in the clinical chemotherapeutic dasatinib which targets BCR-ABL tyrosine kinase with response rates well above 90% [13].IDH acts to catalyze conversion of isocitrate to α-ketoglutarate, regulating various epigenetic states. Mutations in IDH1 and IDH2 are mutually exclusive in AML, carried by approximately 10-40% of patients and result in gain of function to produce the oncometabolite 2-hydroxyglutarate (2HG), compounded with abrogation of normal function. Mutations in IDH1 promote cellular differentiation blockade and progression to leukemia by DNA and histone hypermethylation.Okoye-Okafor et al. conducted a highthroughput screen and structural optimization to identify GSK321, an allosteric inhibitor of mutant IDH1 (Figure 1) [14]. This inhibitor possessed an IC 50 of up to 2.9 nM against the R132G mutation with 46 nM against wt IDH1. Translation to primary R132G

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Coumarin‐Based Aldo‐Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors

Jonnalagadda,

Duan,

Dow

et al. 2024

ChemMedChem

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A series of 7‐substituted coumarin derivatives have been characterized as pan‐aldo‐keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7‐hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3a possessed IC50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits ‘drug‐like’ metabolic stability and half‐life in human and mouse liver microsomes and plasma. Compound 3a was employed as a chemical tool to determine pan‐AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan‐AKR1C inhibitors, 3a demonstrated no radiation sensitization effect in a radiation‐resistant prostate cancer cell line model. Pan‐AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT‐737, daunorubicin or dexamethasone, in two patient‐derived T‐cell ALL and pre‐B‐cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT‐737 and daunorubicin in the T‐cell ALL cell line model. Thus, the inhibitory profile of the AKR1C family inhibitor required to effect enhancement of chemotherapeutic cytotoxicity may be chemotherapeutic agent‐specific in leukemia.

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Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines

Cited by 40 publications

References 34 publications

AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

Small Molecule Inhibitors for Acute Myeloid Leukemia: Where is the Field Heading?

Coumarin‐Based Aldo‐Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors

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