Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to ...this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of
at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to
.
This mini-review focuses on the investigation of novel nitrogen-containing steroid derivatives that are potentially applicable for prostate cancer treatment. It covers the literature of the last ...decade, highlighting the structure of new steroid compounds that exhibit significant activity in prostate cancer cells and possess pharmacological potency. New derivatives of known anti-prostate cancer agents: abiraterone and galeterone, new derivatives of androstane and pregnane modified with nitrogen-containing heterocycles, and some related steroid-derived compounds are discussed in the review.
The conjugation of biologically active molecules is a powerful tool for drug discovery used to target a variety of multifunctional diseases including cancer. Conjugated drugs can provide combination ...therapies in a single multi-functional agent and, by doing so, be more specific and powerful than conventional classic treatments. Steroids are widely used for conjugation with other biological active molecules. This review refers to investigations of steroid conjugates as potential anticancer agents carried out mostly over the past decade. It consists of five parts in which the data concerning structure and anticancer activity of steroid conjugates with DNA alkylating agents, metallocomplexes, approved drugs, some biological active molecules, some natural compounds and related synthetic analogs are described.
Display omitted
•Conjugates of steroids with various biological active molecules are presented.•Steroid conjugates represent privileged structures for development new anti-cancer drugs.•Anti-cancer activity of various steroid conjugates is discussed.
Curcumin attracts huge attention because of its biological properties: it is antiproliferative, antioxidant, anti-inflammatory, immunomodulatory and so on. However, its usage has been limited by poor ...water solubility and low bioavailability. Herein, to solve these problems, we developed curcumin-loaded nanoparticles based on end-capped amphiphilic poly(N-vinylpyrrolidone). Nanoparticles were obtained using the solvent evaporation method and were characterized by dynamic and electrophoretic light scattering, transmission electron (TEM) and atomic force (AFM) microscopy. The average particle size was 200 nm, and the ζ-potential was -4 mV. Curcumin-release studies showed that nanoparticles are stable in aqueous solutions. An in vitro release study showed prolonged action in gastric, intestinal and colonic fluids, consistently, and in PBS. In vitro studies on epidermoid carcinoma and human embryonic kidney cells showed that the cells absorbed more curcumin in nanoparticles compared to free curcumin. Nanoparticles are safe for healthy cells and show high cytotoxicity for glioblastoma cells in cytotoxicity studies in vitro. The median lethal dose was determined in an acute toxicity assay on zebrafish and was 23 μM. Overall, the curcumin-loaded nanoparticles seem promising for cancer treatment.
Human (h) telomerase (TL; EC 2.7.7.49) plays a key role in sustaining cancer cells by means of elongating telomeric repeats at the 3′ ends of chromosomes. Since TL-inhibitor (TI) stand-alone cancer ...therapy has been proven to be remarkably challenging, a polypharmacological approach represents a valid alternative. Here we consider a series of compounds able to inhibit both hTL and the tumor-associated carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII. Compounds 7 and 9 suppressed hTL activity in both cell lysates and human colon cancer cell lines, and prolonged incubation with either 7 or 9 resulted in telomere shortening, cell cycle arrest, replicative senescence, and apoptosis. Enzyme kinetics showed that 7 and 9 are mixed-type inhibitors of the binding of DNA primers and deoxynucleoside triphosphate (dNTP) to the TL catalytic subunit hTERT, which is in agreement with docking experiments. Compound 9 showed antitumor activity in Colo-205 mouse xenografts and suppressed telomerase activity by telomere reduction.
The melanoma origin of cell lines obtained from the axillary lymph node (mel Kas, mel Pet, and mel Lap from patients with a verified diagnosis) was confirmed by the detection of the Melan A ...melanocyte marker expression. A hyperdiploid (2n+) for the mel Kas line; near-diploid (2n), and in some cells near-tertaploid (4n), and even hypo-octaploid (8n) set (172–179 chromosomes) in the mel Pet cell line; and a hypotetraploid (4n−) for the mel Lap line were detected by karyotypic analysis. All three cell lines are tumorigenic; however, mel Pet demonstrates tumor growth in Balb/c nude mice only in the presence of matrigel. All three lines showed a high expression of TUBB3 and PD-L1 markers, while ERa was low (minimum for mel Pet). Significant differences in the expression level were shown for the Cyt molecular marker. In the transplantation of cells to Balb/c nude mice, a stable expression level is observed only for TUBB3. For the rest of the markers, a decrease in their expression level of varying degrees was noted when the cells were growing in solid tumors in vivo. Mutations were detected in oncogenes (BRAF, EZH2, KIT, KRAS, NRAS, ROS1) and tumor suppressor genes (CDKN2A, FAT4, KMT2C, LRP1B, PTEN, PTPRB, TP53). The detailed characterization of the cell lines makes them valuable for various scientific and regulatory experiments, particularly those involving preclinical data on antiproliferative drugs for malignant melanoma or investigations into melanoma cell properties and progression.
The aim of this study was to explore the mechanisms of action of alsevirone in prostate cancer (PC) in vitro and in vivo: CYP17A1 inhibition, cytotoxic, apoptotic, and antitumor effects in comparison ...with abiraterone. The CYP17A1‐inhibitory activity was investigated in rat testicular microsomes using high‐performance liquid chromatography. Testosterone levels were evaluated using enzyme‐linked immunoassay. IC50 values were calculated for PC3, DU‐145, LNCaP, and 22Rv1 cells using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) test. The antitumor effect in vivo was studied in DU‐145 and 22Rv1 subcutaneous xenografts in Balb/c nude mice. Alsevirone reduced the CYP17A1‐inhibitory activity by 98% ± 0.2%. A statistically significant reduction in the testosterone concentration in murine blood was recorded after the 7th administration of 300 mg/kg alsevirone at 0.31 ± 0.03 ng/ml (p < .001) versus 0.98 ± 0.22 ng/ml (p = .392) after abiraterone administration and 1.52 ± 0.49 ng/ml in control animals. Alsevirone was more cytotoxic than abiraterone in DU‐145, LNCaP, and 22Rv1 cells, with IC50 values of 23.80 ± 1.18 versus 151.43 ± 23.70 μM, 22.87 ± 0.54 versus 28.80 ± 1.61 μM, and 35.86 ± 5.63 versus 109.87 ± 35.15 μM, respectively. Alsevirone and abiraterone significantly increased annexin V‐positive, caspase 3/7‐positive, and activated Bcl‐2‐positive cells. In 22Rv1 xenografts, alsevirone 300 mg/kg × 10/24 h per os inhibited tumor growth: on Day 9 of treatment, tumor growth inhibition = 59% (p = .022). Thus, alsevirone demonstrated significant antitumor activity associated with CYP17A1 inhibition, apoptosis in PC cells, and testosterone reduction.
The mechanisms of action of alsevirone in prostate cancer (PC) were studied in vitro and in vivo, analyzing CYP17A1 inhibition and cytotoxic, apoptotic, and antitumor effects in comparison with abiraterone. Alsevirone induced intrinsic apoptosis with overexpression of proapoptotic proteins and showed potent antiproliferative activity in human PC cells and in 22Rv1 subcutaneous xenografts in Balb/c nude mice. Alsevirone may serve as a potential agent for the treatment of PC.
Proteasome inhibitor bortezomib is an anticancer agent approved for treatment of multiple myeloma and mantle cell lymphoma. However, its application in other types of cancer, primarily in solid ...tumors, is limited due to poor pharmacokinetics, inefficient tissue penetration, low stability and frequent adverse effects. In the present study, a novel micellar nano-scaled delivery system was manufactured, composed of amphiphilic poly(N-vinylpyrrolidone) nanoparticles loaded with bortezomib. Similar nanoparticles loaded with prothionamide, a drug without anticancer effect, were used as control. The size and zeta potential of the obtained polymeric micelles were measured by dynamic light scattering. Bortezomib-loaded micelles exhibited significant cytotoxic activity
in monolayer tumor cell cultures (IC
~6.5 µg/ml) and in 3D multicellular tumor spheroids (IC
~8.5 µg/ml) of human glioblastoma cell lines U87 and T98G. Additionally, the toxic effects
were studied in zebrafish
embryos, with an estimated 50% lethal concentration of 0.1 mg/ml. Considering that bortezomib and other molecules from the class of proteasome inhibitors are potent antitumor agents, nanodelivery approach can help reduce adverse effects and expand the range of its applications for treatment of various oncological diseases.
Steroid derivatives modified with nitrogen containing heterocycles attract attention as anticancer agents for prostate cancer treatment. In this study we have developed a simple and convenient ...procedure for preparation of 17(20)‐21‐norpregnene and androst‐16‐ene 2’‐oxazolinyl and 2’‐benzoxazolyl derivatives, based on the reaction of an appropriately modified steroidal carboxylic acid with 1,2‐amino alcohols or o‐aminophenol. Using this method we conducted synthesis a series of new steroid hybrids differing either in the structure of steroidal part, or in the structure of nitrogen containing heterocycle (23 compounds in total). Some of compounds revealed high anti‐proliferative activity in prostate carcinoma LNCaP and PC‐3 cells, exceeding that for well‐known agents abiraterone and galeterone. Oxazoline containing derivative of 17(20)‐21‐norpregnene potently stimulated apoptosis in DU‐145 cells and inhibited the growth of tumors in DU‐145 and 22Rv1 derived xenograft models in direct comparison with abiraterone.
The simple and convenient procedure for preparation of 17(20)‐21‐norpregnene and androst‐16‐ene 2’‐oxazolinyl, 2’‐benzoxazolyl, and 2’‐benzimidazolyl derivatives, based on the reaction of an appropriately modified steroidal carboxylic acid with 1,2‐amino alcohols, o‐aminophenol, or o‐phenylenediamine is developed. The synthesis a series of new steroid hybrids differing either in the structure of steroidal part, or in the structure of nitrogen containing heterocycle was carried out. Some of synthesized compounds revealed high anti‐proliferative activity in prostate carcinoma cells; the selected compound of this series exhibited strong anti‐apoptotic effects in prostate carcinoma DU‐145 cells and inhibited tumor growth in mouse xenograft models.
