International Journal of Molecular Sciences

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Special Issue: “Novel Researches and Perspectives on Prostate Cancer”

by Giovanni Luca Beretta

Int. J. Mol. Sci. 2024, 25(4), 2054; https://doi.org/10.3390/ijms25042054 - 08 Feb 2024

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Abstract

Prostate cancer (PCa) represents the second most diagnosed tumor and the fifth most common cause of cancer death in men globally [...] Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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13 pages, 3643 KiB

Open AccessArticle

Prostate-Specific Membrane Antigen (PSMA) Expression Predicts Need for Early Treatment in Prostate Cancer Patients Managed with Active Surveillance

by Elham Ahmadi, Simon Wang, Mohammad Gouran-Savadkoohi, Georgia Douvi, Naghmeh Isfahanian, Nicole Tsakiridis, Brent E. Faught, Jean-Claude Cutz, Monalisa Sur, Satish Chawla, Gregory R. Pond, Gregory R. Steinberg, Ian Brown and Theodoros Tsakiridis

Int. J. Mol. Sci. 2023, 24(22), 16022; https://doi.org/10.3390/ijms242216022 - 07 Nov 2023

Cited by 1 | Viewed by 1061

Abstract

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate–glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early [...] Read more.

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate–glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83–13.94] and HR: 2.44, [CI 95%: 1.10–5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies. Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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18 pages, 3551 KiB

Open AccessArticle

Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications

by José María Mora-Rodríguez, Belén G. Sánchez, Alba Sebastián-Martín, Alba Díaz-Yuste, Manuel Sánchez-Chapado, Ana María Palacín, Carlos Sánchez-Rodríguez, Alicia Bort and Inés Díaz-Laviada

Int. J. Mol. Sci. 2023, 24(21), 15626; https://doi.org/10.3390/ijms242115626 - 26 Oct 2023

Cited by 1 | Viewed by 1087

Abstract

In this study, we examined the metabolic adaptations of a chemoresistant prostate cancer cell line in comparison to a sensitive cell line. We utilized prostate cancer LNCaP cells and subjected them to a stepwise increase in the antiandrogen 2-hydroxy-flutamide (FLU) concentration to generate [...] Read more.

In this study, we examined the metabolic adaptations of a chemoresistant prostate cancer cell line in comparison to a sensitive cell line. We utilized prostate cancer LNCaP cells and subjected them to a stepwise increase in the antiandrogen 2-hydroxy-flutamide (FLU) concentration to generate a FLU-resistant cell line (LN-FLU). These LN-FLU cells displayed characteristics of cancer stem cells, exhibited drug resistance, and showed a significantly reduced expression of Cyclin D1, along with the overexpression of p16, pointing to a proliferation arrest. In comparing the cancer stem-like LN-FLU cells to the LNCaP cells, we observed a decrease in the expression of CTP-choline cytidylyl transferase α (CCTα), as well as a decline in choline kinase, suggesting altogether a downregulation of the phosphatidylcholine biosynthetic pathway. In addition, we found decreased levels of the protein methyl transferase PRMT2 and the upregulation of the histone deacetylase Sirtuin1 (Sirt1). Analysis of the human prostate cancer samples revealed similar results in a population with high expressions of the stem cell markers Oct4 and ABCB1A1. Our findings suggest that the adaptation of prostate cancer cells to antiandrogens could induce reprogramming into stem cells that survive in a low phosphocholine metabolism and cell cycle arrest and display drug resistance. Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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30 pages, 3893 KiB

Open AccessArticle

Synthesis, ¹²³I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures

by Lutfi A. Hasnowo, Maria S. Larkina, Evgenii Plotnikov, Vitalina Bodenko, Feruza Yuldasheva, Elena Stasyuk, Stanislav A. Petrov, Nikolai Y. Zyk, Aleksei E. Machulkin, Nikolai I. Vorozhtsov, Elena K. Beloglazkina, Valentine G. Nenajdenko, Vladimir Tolmachev, Anna Orlova, Alexander G. Majouga and Mekhman S. Yusubov

Int. J. Mol. Sci. 2023, 24(15), 12206; https://doi.org/10.3390/ijms241512206 - 30 Jul 2023

Cited by 1 | Viewed by 1376

Abstract

Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, [...] Read more.

Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [¹²⁷I]PSMA-m-IB and [¹²⁷I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)₃ group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [¹²³I]PSMA-p-IB was higher than that of [¹²³I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [¹²³I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [¹²³I]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [¹²³I]PSMA-p-IB showed less accumulation than [¹⁷⁷Lu]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice. Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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15 pages, 2435 KiB

Open AccessArticle

Excitation of a Single Compound by Light and Ultrasound Enhanced the Long-Term Cure of Mice Bearing Prostate Tumors

by Joseph Cacaccio, Farukh A. Durrani, Ishaan Kumar, Mykhaylo Dukh, Susan Camacho, Zahra Fayazi, Adam Sumlin, Eric Kauffman, Khurshid Guru and Ravindra K. Pandey

Int. J. Mol. Sci. 2023, 24(13), 10624; https://doi.org/10.3390/ijms241310624 - 25 Jun 2023

Cited by 1 | Viewed by 1088

Abstract

Current treatment for prostate cancer is dependent on the stages of the cancer, recurrence, and genetic factors. Treatment varies from active surveillance or watchful waiting to prostatectomy, chemotherapy, and radiation therapy in combination or alone. Although radical prostate cancer therapy reduces the advancement [...] Read more.

Current treatment for prostate cancer is dependent on the stages of the cancer, recurrence, and genetic factors. Treatment varies from active surveillance or watchful waiting to prostatectomy, chemotherapy, and radiation therapy in combination or alone. Although radical prostate cancer therapy reduces the advancement of the disease and its mortality, the increased disease treatment associated morbidity, erectile dysfunction, and incontinence affect the quality of life of cancer survivors. To overcome these problems, photodynamic therapy (PDT) has previously been investigated using Photofrin^TM as a photosensitizer (PS). However, Photofrin-PDT has shown limitations in treating prostate cancer due to its limited tumor-specificity and the depth of light penetration at 630 nm (the longest wavelength absorption of Photofrin^TM). The results presented herein show that this limitation can be solved by using a near infrared (NIR) compound as a photosensitizer (PS) for PDT and the same agent also acts as a sonosensitizer for SDT (using ultrasound to activate the compound). Compared to light, ultrasound has a stronger penetration ability in biological tissues. Exposing the PS (or sonosensitizer) to ultrasound (US) initiates an electron-transfer process with a biological substrate to form radicals and radical ions (type I reaction). In contrast, exposure of the PS to light (PDT) generates singlet oxygen (type II reaction). Therefore, the reactive oxygen species (ROS) produced by SDT and PDT follow two distinct pathways, i.e., type I (oxygen independent) and type II (oxygen dependent), respectively, and results in significantly enhanced destruction of tumor cells. The preliminary in vitro and in vivo results in a PC3 cell line and tumor model indicate that the tumor specificality of the therapeutic agent(s) can be increased by targeting galectin-1 and galectin-3, known for their overexpression in prostate cancer. Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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20 pages, 4613 KiB

Open AccessArticle

Old Drug, New Delivery Strategy: MMAE Repackaged

by Hanane Lahnif, Tilmann Grus, Evangelia-Alexandra Salvanou, Elisavet Deligianni, Dimitris Stellas, Penelope Bouziotis and Frank Rösch

Int. J. Mol. Sci. 2023, 24(10), 8543; https://doi.org/10.3390/ijms24108543 - 10 May 2023

Cited by 2 | Viewed by 2194

Abstract

Targeting therapy is a concept that has gained significant importance in recent years, especially in oncology. The severe dose-limiting side effects of chemotherapy necessitate the development of novel, efficient and tolerable therapy approaches. In this regard, the prostate specific membrane antigene (PSMA) has [...] Read more.

Targeting therapy is a concept that has gained significant importance in recent years, especially in oncology. The severe dose-limiting side effects of chemotherapy necessitate the development of novel, efficient and tolerable therapy approaches. In this regard, the prostate specific membrane antigene (PSMA) has been well established as a molecular target for diagnosis of, as well as therapy for, prostate cancer. Although most PSMA-targeting ligands are radiopharmaceuticals used in imaging or radioligand therapy, this article evaluates a PSMA-targeting small molecule–drug conjugate, and, thus, addresses a hitherto little-explored field. PSMA binding affinity and cytotoxicity were determined in vitro using cell-based assays. Enzyme-specific cleavage of the active drug was quantified via an enzyme-based assay. Efficacy and tolerability in vivo were assessed using an LNCaP xenograft model. Histopathological characterization of the tumor in terms of apoptotic status and proliferation rate was carried out using caspase-3 and Ki67 staining. The binding affinity of the Monomethyl auristatin E (MMAE) conjugate was moderate, compared to the drug-free PSMA ligand. Cytotoxicity in vitro was in the nanomolar range. Both binding and cytotoxicity were found to be PSMA-specific. Additionally, complete MMAE release could be reached after incubation with cathepsin B. In vivo, the MMAE conjugate displayed good tolerability and dose-dependent inhibition of tumor growth. Immunohistochemical and histological studies revealed the antitumor effect of MMAE.VC.SA.617, resulting in the inhibition of proliferation and the enhancement of apoptosis. The developed MMAE conjugate showed good properties in vitro, as well as in vivo, and should, therefore, be considered a promising candidate for a translational approach. Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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15 pages, 2994 KiB

Open AccessArticle

MDR1 Inhibition Reverses Doxorubicin-Resistance in Six Doxorubicin-Resistant Canine Prostate and Bladder Cancer Cell Lines

by Eva-Maria Packeiser, Leoni Engels, Ingo Nolte, Sandra Goericke-Pesch and Hugo Murua Escobar

Int. J. Mol. Sci. 2023, 24(9), 8136; https://doi.org/10.3390/ijms24098136 - 02 May 2023

Cited by 3 | Viewed by 1839

Abstract

Acquired chemoresistance during chemotherapy, often accompanied by cross- and multi-resistance, limits therapeutic outcomes and leads to recurrence. In order to create in vitro model systems to understand acquired doxorubicin-resistance, we generated doxorubicin-resistant sublines of canine prostate adenocarcinoma and urothelial cell carcinoma cell lines. [...] Read more.

Acquired chemoresistance during chemotherapy, often accompanied by cross- and multi-resistance, limits therapeutic outcomes and leads to recurrence. In order to create in vitro model systems to understand acquired doxorubicin-resistance, we generated doxorubicin-resistant sublines of canine prostate adenocarcinoma and urothelial cell carcinoma cell lines. Chemoresistance to doxorubicin, cross-resistance to carboplatin, and the reversibility of the acquired resistance by the specific MDR1-inhibitor tariquidar were quantified in metabolic assays. Resistance mechanisms were characterized by expression of the efflux transporters MDR1 and RALBP1, as well as the molecular target of doxorubicin, TOP2A, with qPCR and Western blotting. Six out of nine cell lines established stable resistance to 2 µM doxorubicin. Drug efflux via massive MDR1 overexpression was identified as common, driving resistance mechanism in all sublines. MDR1 inhibition with tariquidar extensively reduced or reversed the acquired, and also partly the parental resistance. Three cell lines developed additional, non-MDR1-dependent resistance. RALBP1 was upregulated in one resistant subline at the protein level, while TOP2A expression was not altered. Combination therapies aiming to inhibit MDR1 activity can now be screened for synergistic effects using our resistant sublines. Nevertheless, detailed resistance mechanisms and maintained molecular target expression in the resistant sublines are still to be examined. Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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Open AccessReview

Emerging Immunotherapy Approaches for Treating Prostate Cancer

by Lingbin Meng, Yuanquan Yang, Amir Mortazavi and Jingsong Zhang

Int. J. Mol. Sci. 2023, 24(18), 14347; https://doi.org/10.3390/ijms241814347 - 20 Sep 2023

Cited by 3 | Viewed by 1872

Abstract

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, [...] Read more.

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) T cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes from completed clinical trials and strategies to improve clinical efficacy that are being tested in ongoing clinical trials. Imperative endeavors include biomarker discovery for patient selection, deciphering resistance mechanisms, refining cellular therapies such as CAR T cells, and early-stage intervention were reviewed. These ongoing efforts instill optimism that immunotherapy may eventually deliver significant clinical benefits and expand treatment options for patients with advanced prostate cancer. Full article

(This article belongs to the Special Issue Novel Researches and Perspectives on Prostate Cancer)

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