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Costello, Leslie C.; Franklin, Renty B.

doi:10.1186/1476-4598-5-17

Cited by 328 publications

(242 citation statements)

References 61 publications

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“…Figure 1 shows a ventral view of the TRAMP prostate with advanced tumors and lymph node with metastases. Figure 2 presents typical in vivo 1 H MRSI spectra taken from a patient with surgically proven prostate cancer in the lateral posterior aspect of the right midgland. As previously described, 1 H MRSI spectra from the normal peripheral zone contain high level of citrate and low choline and creatine.…”

Section: Resultsmentioning

confidence: 99%

“…Figure 2 presents typical in vivo 1 H MRSI spectra taken from a patient with surgically proven prostate cancer in the lateral posterior aspect of the right midgland. As previously described, 1 H MRSI spectra from the normal peripheral zone contain high level of citrate and low choline and creatine. 6 In contrast, the malignant tissue exhibits a significant, pathologic grade dependent decrease in citrate accompanied by increased levels of choline containing phospholipids metabolites.…”

Section: Resultsmentioning

confidence: 99%

“…It is well established that zinc and citrate levels are virtually always markedly decreased in prostate cancer as compared with normal and benign prostate (for reviews see ref. [1][2][3][4]. This relationship currently, in our view, is the most consistent and persistent "hallmark" characteristic of human prostate cancer, which distinguishes prostate cancer from normal and benign prostate.…”

Section: Introductionmentioning

confidence: 99%

“…The ZIP1/zinc/citrate decrease constitutes a "genetic/metabolic" transformation of normal prostate cells to malignant cells in the development of prostate cancer. 1,5 Despite this important relationship, the coupled ZIP1/zinc/citrate relationship has not been determined or established in any of the existing animal models that purport to represent human prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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Human prostate cancer ZIP1/zinc/citrate genetic/metabolic relationship in the TRAMP prostate cancer animal model

Costello

Franklin

Zou

et al. 2011

Cancer Biology & Therapy

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Prostate cancer is the second leading cause of cancer deaths among men. The availability of animal models that represent the events and factors that exist in the natural history and biology of human prostate cancer is essential in dealing with prostate cancer. In recent decades and presently, emphasis has been directed at the development and employment of prostate cancer induced in transgenic mice. However, the important consistent hallmark characteristic and event of decrease in zinc and citrate and downregulation of ZIP1 zinc transporter in prostate malignancy has not been studied or identified in any animal model. We investigated the status of these parameters in TRAMP tumors as compared with human prostate cancer. The results show that citrate levels are markedly decreased in the developing and advancing stages of malignancy in TRAMP. Zinc levels are also decreased and ZIP1 transporter is lost in TRAMP tumors. In vitro studies show that zinc treatment of TRAMP C2 cells exhibits cytotoxic effects. Collectively, these results mimic the ZIP1, zinc, and citrate status and relationship that exist in human prostate cancer. This is the first report that establishes the existence of the human prostate zinc/citrate hallmark characteristic and relationship in an animal model. It now appears that the TRAMP model will be suitable for studies relating to the implications and role of zinc-and citraterelated metabolism in the development and progression of human prostate cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Human prostate cancer ZIP1/zinc/citrate genetic/metabolic relationship in the TRAMP prostate cancer animal model

Costello

Franklin

Zou

et al. 2011

Cancer Biology & Therapy

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“…9 Due to the lack of appropriate analytical tools to follow cisplatin inside live cells, 5 most studies were carried out in simple buffers. The cellular environment, however, is 25 much more complex containing numerous small molecules, nucleic acids and proteins that compete for cisplatin binding. 10,11 The cisplatin concentration inside cells is estimated to be just nanomolar to low micromolar.…”

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confidence: 99%

Citrate inhibition of cisplatin reaction with DNA studied using fluorescently labeled oligonucleotides: implication for selectivity towards guanine

2013

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The reaction between cisplatin and DNA is conveniently studied using fluorescently labeled oligonucleotides and gel electrophoresis; as an example of application, the inhibition of this reaction by citrate is demonstrated, which might 10 increase selectivity of cisplatin towards guanine over adenine.Cisplatin is one of the most successful and important anticancer drugs. [1][2][3][4] It is generally accepted that DNA is the molecular target of cisplatin, forming intrastrand crosslinked guanines, 1 although the exact mechanism is still under 15 debate. 5 A lot has already been learned about the reaction between DNA and cisplatin. 6 The difference in the Clconcentration outside a cell (~100 mM) and inside (~4-12 mM) might facilitate dissociation of Cl -and adding water inside the cell. 1 The aquated product is trapped in the cell to 20 react with various nucleophilic species including DNA. 7,8 Mechanisms related to electron transfer have also been proposed. 9 Due to the lack of appropriate analytical tools to follow cisplatin inside live cells, 5 most studies were carried out in simple buffers. The cellular environment, however, is 25 much more complex containing numerous small molecules, nucleic acids and proteins that compete for cisplatin binding. 10,11 The cisplatin concentration inside cells is estimated to be just nanomolar to low micromolar. 5 Many cellular compounds can tightly bind to cisplatin, leaving little 30 free cisplatin for DNA binding. Examples of such competitors include sulfer containing proteins, 12,13 glutathione (GSH), 14,15 and even inorganic anions. 16 Before cisplatin can react with DNA, it has to be released from these competing ligands. 17 Many an initial test, we employed FAM-labeled 15-mer DNA homopolymers. The DNAs were mixed with increasing concentrations of cisplain for 16 h and the samples were then loaded into a non-denaturing polyacrylamide gel. A gradual shift of the FAM-A15 band with reduced mobility was 70 observed with increasing cisplatin concentration ( Figure 1A), suggesting reaction between this DNA and cisplatin. The Pt-DNA adduct did not migrate as a single band, suggesting the presence of a broad range of products, possibly due to different levels and positions of platination. Fluorescence 75 quenching was also observed, especially at high Pt concentrations. On the other hand, no shift was observed with FAM-T15 and its fluorescence just dropped in intensity with increasing cisplatin concentration ( Figure 1B). Reactions also occurred with FAM-C15 and its product distribution pattern 80 was quite different, where discrete bands were observed at low Pt concentrations and the gel smeared at high Pt concentrations ( Figure 1C). Finally, FAM-G15 showed slightly smeared gel even for the initial free DNA, possibly due to its tendency to form various secondary structures such as inter- 85 and intra-molecular quadruplexes ( Figure 1D). Mass spectrum of FAM-G15 showed a few high molecular weight species, consistent with the smeared gel ( Figure S1, ESI). Addition of cispla...

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Assessments of prostate cancer cell functions highlight differences between a pan‐PI3K/mTOR inhibitor, gedatolisib, and single‐node inhibitors of the PI3K/AKT/mTOR pathway

Sen,

Khan,

Rossetti

et al. 2024

Molecular Oncology

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Metastatic castration‐resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co‐targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi‐node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single‐node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti‐proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM‐controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN‐dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2− advanced breast cancer.

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Untitled

Cited by 328 publications

References 61 publications

Human prostate cancer ZIP1/zinc/citrate genetic/metabolic relationship in the TRAMP prostate cancer animal model

Human prostate cancer ZIP1/zinc/citrate genetic/metabolic relationship in the TRAMP prostate cancer animal model

Citrate inhibition of cisplatin reaction with DNA studied using fluorescently labeled oligonucleotides: implication for selectivity towards guanine

Assessments of prostate cancer cell functions highlight differences between a pan‐PI3K/mTOR inhibitor, gedatolisib, and single‐node inhibitors of the PI3K/AKT/mTOR pathway

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