Z-1,1-Dichloro-2,3-diphenylcyclopropanes block human prostate carcinoma cell proliferation, inhibit prostate-specific antigen expression, and initiate apoptosis

Balachandran, Raghavan; Grant, Stephen G.; Welsh, Manda J.; Day, Billy W.

doi:10.1002/1097-0045(20001201)45:4<277::aid-pros1>3.0.co;2-w

Cited by 2 publications

(5 citation statements)

References 48 publications

(48 reference statements)

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“…The highest concentration tested for any of the three test agents was 10 µM. Unlike our previous results in human prostate carcinoma cells [20], A II was inactive at concentrations of ≤ 10 uM. Colchicine yielded 50% growth inhibitory (GI 50 ) values in the mid-nanomolar range but no detectable total growth inhibitory (TGI; the GI 100 ) nor 50% lethality (LC 50 ; reduction of cell number to half that originally plated) concentrations.…”

Section: Growth Inhibition Studiescontrasting

confidence: 60%

“…Our previous studies of the actions of A II and 2-(4-methoxyphenyl)-A II against the human prostate cancer cell lines PC-3 and LNCaP showed each agent to be antiproliferative against these cells at low micromolar concentrations. 2-(4-methoxyphenyl)-A II induces G 2 /M accumulation, but only weakly induces apoptosis in both LNCaP and PC-3 cell lines [20].…”

Section: Discussionmentioning

confidence: 96%

“…We have previously noted by flow cytometry that by 2-(4-methoxyphenyl)-A II causes slight increases in the hypodiploid population, an indicator of apoptosis, in human prostate cancer cells [20]. We therefore postulated that the concentration-dependent TRAMP cell growth inhibition exerted by this agent was due to induction of the cell's apoptosis machinery.…”

Section: Apoptosis Elisa Assaymentioning

confidence: 97%

“…In breast cancer cell lines, A II disrupts microtubules and causes apoptosis [11,19]. Most recently, we have shown A II at low concentrations to block PSA production and cell proliferation in the LNCaP human androgen-responsive prostate cancer cell line [20].…”

Section: Introductionmentioning

confidence: 99%

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(Z)-1,1-Dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane induces concentration-dependent growth inhibition, apoptosis, and coordinates regulation of apoptotic genes in TRAMP cells

Thomas

Grant

Pflug

et al. 2008

Urologic Oncology: Seminars and Original Investigations

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(Z)-1-1-Dichloro-2,3-diphenylcyclopropane (A(II)) and (Z)-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane [2-(4-methoxyphenyl)-A(II)] inhibit tubulin polymerization, PSA production, and the proliferation of human prostate cancer cells. The actions of the agents were studied in three transgenic adenocarcinomas of the mouse prostate (TRAMP) cell lines. Antiproliferative potencies were determined and cells treated with the more potent 2-(4-methoxyphenyl)-A(II) were examined for induction of apoptosis. Microarray analyses were conducted to determine the apoptosis-related genes up- and down-regulated by the agent. 2-(4-Methoxyphenyl)-A(II) concentration-dependently inhibited growth of all three cell lines. Fifty percent and 100% growth inhibitory and 50% lethal concentrations were determined to be 0.3, 1.5, and 5 muM, respectively. Minimum detectable apoptosis-inducing concentrations by ELISA were 0.10 to 0.14 muM. PARP cleavage and two-color flow cytometry assays verified apoptosis induction. Microarray analyses showed Bok and Siva-pending to be up-regulated and that Birc, Dad1, and Atf5 were down-regulated. 2-(4-methoxyphenyl)-A(II) inhibits proliferation and induces apoptosis in the in vivo-adaptable TRAMP cells, suggesting the compound should be further examined in preclinical models.

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Section: Growth Inhibition Studiescontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 96%

Section: Apoptosis Elisa Assaymentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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(Z)-1,1-Dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane induces concentration-dependent growth inhibition, apoptosis, and coordinates regulation of apoptotic genes in TRAMP cells

Thomas

Grant

Pflug

et al. 2008

Urologic Oncology: Seminars and Original Investigations

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“…The colchicine site‐binding agent curacin A induced apoptosis via a mechanism associated with cleavage of caspases, α‐spectrin, and changes in the expression of Bcl‐x S/L in PC‐3 cells, a phenotype that differs dramatically from that caused by TH‐169. PC‐3 cells have also been shown to undergo internucleosomal DNA fragmentation in the presence of some other colchicine site‐binding microtubule‐perturbing agents (14). Presumably, TH‐169 binds to a novel site, or several different sites, on tubulins.…”

Section: Discussionmentioning

confidence: 99%

Tubulin‐Perturbing Naphthoquinone Spiroketals

Balachandran¹,

Hopkins²,

Thomas³

et al. 2008

Chem Biol Drug Des

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Several natural and synthetic naphthoquinone spiroketals are potent inhibitors of the thioredoxin-thioredoxin reductase redox system. Based on the antimitotic and weak antitubulin actions noted for SR-7 ([8-(furan-3-ylmethoxy)-1-oxo-1,4-dihydronaphthalene-4-spiro-2'-naphtho[1'',8''-de][1',3'][dioxin]), a library of related compounds was screened for tubulin-perturbing properties. Two compounds, TH-169 (5'-hydroxy-4'H-spiro[1,3-dioxolane-2,1'-naphthalen]-4'-one) and TH-223 (5'-methoxy-4'H-spiro[1,3-dioxane-2,1'-naphthalen]-4'-one), had substantial effects on tubulin assembly and were antiproliferative at low micromolar concentrations. TH-169 was the most potent at blocking GTP-dependent polymerization of 10 mum tubulin in vitro with a remarkable 50% inhibitory concentration of ca. 400 nm. It had no effect on paclitaxel-induced microtubule assembly and did not cause microtubule hypernucleation. TH-169 failed to compete with colchicine for binding to beta-tubulin. The 50% antiproliferative concentration of TH-169 against human cancer cells was at or slightly below 1 mum. Flow cytometry showed that 1 mum TH-169 caused an increase in G(2)/M and hypodiploid cells. TH-169 eliminated the PC-3 cells' polyploid population and increased their expression of p21(WAF1) and Hsp70 in a concentration-dependent manner. The antiproliferative effect of TH-169 was irreversible and independent of changes in caspases, actin, tubulin, glyceraldehyde phosphate dehydrogenase or Bcl-x(S/L). This structurally simple naphthoquinone spiroketal represents a small molecule, tubulin-interactive agent with a novel apoptotic pathway and attractive biological function.

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Z-1,1-Dichloro-2,3-diphenylcyclopropanes block human prostate carcinoma cell proliferation, inhibit prostate-specific antigen expression, and initiate apoptosis

Cited by 2 publications

References 48 publications

(Z)-1,1-Dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane induces concentration-dependent growth inhibition, apoptosis, and coordinates regulation of apoptotic genes in TRAMP cells

(Z)-1,1-Dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane induces concentration-dependent growth inhibition, apoptosis, and coordinates regulation of apoptotic genes in TRAMP cells

Tubulin‐Perturbing Naphthoquinone Spiroketals

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