Natural Chalcones and Derivatives in Colon Cancer: Pre-Clinical Challenges and the Promise of Chalcone-Based Nanoparticles.

Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development and progression of colon cancer makes them invaluable as targeted therapeutics. Nevertheless, it is crucial to recognize that although chalcones exhibit promise, further pre-clinical studies are required to validate their efficacy and safety. The journey toward effective colon cancer treatment is multifaceted, involving considerations such as optimizing the sequencing of therapeutic agents, comprehending the resistance mechanisms, and exploring combination therapies incorporating chalcones. Furthermore, the integration of nanoparticle-based drug delivery systems presents a novel avenue for enhancing the effectiveness of chalcones in colon cancer treatment. This review delves into the mechanisms of action of natural chalcones and some derivatives. It highlights the challenges associated with their use in pre-clinical studies, while also underscoring the advantages of employing chalcone-based nanoparticles for the treatment of colon cancer.

Synthesis and biological evaluation of chalcone-polyamine conjugates as novel vectorized agents in colorectal and prostate cancer chemotherapy.

The aim of this study was to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. Indeed, it is well-known that polyamine transport system is upregulated in tumor cells. 3',4,4',5'-tetramethoxychalcone was selected as parent chalcone since it was found to be an efficient anti-proliferative agent on various cancer cells. A series of five chalcone-polyamine conjugates was obtained using the 4-bromopropyloxy-3',4',5'-trimethoxychalcone as a key intermediate. Chalcone core and polyamine tails were fused through an amine bond. These conjugates were found to possess a marked in vitro antiproliferative effect against colorectal (HT-29 and HCT-116) and prostate cancer (PC-3 and DU-145) cell lines. The most active conjugate (compound 8b) was then chosen for further biological evaluations to elucidate mechanisms responsible for its antiproliferative activity. Investigations on cell cycle distribution revealed that this conjugate can prevent the proliferation of human colorectal and prostate cancer cells by blocking the cell cycle at the G1 and G2 phase, respectively. Flow cytometry analysis revealed a sub-G1 peak, characteristic of apoptotic cell population and our inquiries highlighted apoptosis induction at early and later stages through several pro-apoptotic markers. Therefore, this chalcone-N1-spermidine conjugate could be considered as a promising agent for colon and prostatic cancer adjuvant therapy.

Contributions of a blended learning based on peer evaluation for teaching drug-drug interactions to undergraduate pharmacy students.

BACKGROUND: Numerous studies have pointed out the need for better training of healthcare professionals in drug-drug interactions management in order to minimize adverse drugs reactions impacts on patients. The aim of this study was to evaluate the benefits of a blended learning strategy based on peer evaluation (PE) for teaching drug-drug interactions to undergraduate pharmacy students. METHODS: Third-year pharmacy students (n = 72) from the University of Limoges were involved in a hybrid teaching using the Moodle platform (2.9 version). After the theoretical lectures, an online activity was proposed to students. Each student submitted a report addressing a clinical case for peer evaluation. Students evaluated the pedagogical approach using an online survey. Quantitative benefits were assessed from students randomly assigned into two groups: PE in pharmacodynamics items (PE-PD) or PE in pharmacokinetics items (PE-PK). During this activity, three marks were given: one from peers for their evaluation work and two from teachers for oral group presentation of the clinical cases and for the final written examination. Statistics were performed using two-tailed unpaired t-test and significance was set for p < 0.05. RESULTS: Only a few students (n = 14, 20.6%) were aware of the peer evaluation principle and even less, only one student (n = 1, 1.5%), had already encountered it. Students considered that they benefited from this evaluation (n = 65, 95.6%); from their work being reviewed (n = 62, 91.2%) and that they participated in improving their classmates understanding (n = 59, 86.8%). Peers' allocated marks were similar in the two PE groups (PE-PD = 17.4 ± 1.4; PE-PK = 17.3 ± 1.4). Teachers' marks for oral presentation were significantly lower for pharmacodynamics than for pharmacokinetics items (PE-PD = 15.2 ± 1.2; PE-PK = 16.1 ± 2.1; p < 0.05). The final examination marks were equivalent in both groups (PE-PD = 11.0 ± 2.1; PE-PK = 11.2 ± 1.9). CONCLUSIONS: Besides the fact that a major short-term quantitative improvement was not detected, our teaching approach was qualified as being a positive and stimulating learning tool by students.

Enhancement of hydrosolubility and in vitro antiproliferative properties of chalcones following encapsulation into ß-cyclodextrin/cellulose-nanocrystal complexes.

This paper describes the preparation of two chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes and the study of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of this work was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals. These latter were linked, through ionic interactions, to a cationic derivative of ß-cyclodextrins whose lipophilic cavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones. Then, chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferative activities, compared to the corresponding free-chalcones.

Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents.

The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2) were selected as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then, chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be considered as promising compounds for colon and prostatic cancer adjuvant therapy.

Resistance to 3-HTMC-Induced Apoptosis Through Activation of PI3K/Akt, MEK/ERK, and p38/COX-2/PGE2 Pathways in Human HT-29 and HCT116 Colorectal Cancer Cells.

Increasing incidence and mortality of colorectal cancer brings the necessity to uncover new possibilities in its prevention and treatment. Chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. In this study, we investigated the effects of the synthetic chalcone derivative 3-hydroxy-3',4,4',5'-tetra-methoxy-chalcone (3-HTMC) on proliferation, cell cycle distribution, apoptosis, and its mechanism of action in human colorectal HT-29 (COX-2 sufficient) and HCT116 (COX-2 deficient) cancer cells. We showed that 3-HTMC decreased cell viability in a dose-dependent manner with a more potent antiproliferative effect on HCT116 than HT-29 cells. Flow cytometric analysis revealed G2 /M cell cycle accumulation in HT-29 cells and significant G2 /M arrest in HCT116 cells with a subsequent apoptosis shown by appearance of Sub-G1 peak. We demonstrated that 3-HTMC treatment on both cell lines induced apoptotic process associated with overexpression of death receptor DR5, activation of caspase-8 and -3, PARP cleavage, and DNA fragmentation. In addition, 3-HTMC induced activation of PI3K/Akt and MEK/ERK principal survival pathways which delay 3-HTMC-induced apoptosis in both cell lines. Furthermore, COX-2 overexpression in HT-29 cells contributes to apoptosis resistance which explains the difference of sensitivity between HT-29 and HCT116 cells to 3-HTMC treatment. Even if resistance mechanisms to apoptosis reduced chalcone antitumoral potential, our results suggest that 3-HTMC may be considered as an interesting compound for colorectal cancer therapy or chemoprevention. J. Cell. Biochem. 117: 2875-2885, 2016. © 2016 Wiley Periodicals, Inc.

Delivery of tanshinone IIA and α-mangostin from gold/PEI/cyclodextrin nanoparticle platform designed for prostate cancer chemotherapy.

A new anti-cancer drug delivery system, based on gold nanoparticles, has been designed for hydrophobic active compounds. The system is a conjugate of gold/polyethyleneimine (AuNPs/PEI) nanoparticles and sulphated ß-cyclodextrin (CD). Anionic cyclodextrin was attached to the positively charged AuNPs/PEI nanoparticles by ionic bonds. Tanshinone IIA and α-mangostin were extracted, purified and encapsulated into the AuNPs/PEI/CD nanoparticles. In vitro preliminary cell viability assays against prostate cancer cell lines PC-3 and DU145 showed that encapsulation resulted in increased cytotoxicity.

2'-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells.

Prostate cancer is the most common malignant cancer in men and the second leading cause of cancer deaths. Previously, we have shown that 2'-hydroxy-4-methylsulfonylchalcone (RG003) induced apoptosis in prostate cancer cell lines PC-3 and DU145. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, some cancer cells are resistant to TRAIL treatment. PC-3 and LNCaP prostatic cancer cell lines have been reported to be resistant to TRAIL-induced apoptosis. Here, we show for the first time that RG003 overcomes TRAIL resistance in prostate cancer cells. RG003 can enhance TRAIL-induced apoptosis through DR5 upregulation and downregulation of Bcl-2, PI3K/Akt, NF-κB, and cyclooxygenase-2 (COX-2) survival pathways. When used in combined treatment, RG003 and TRAIL amplified TRAIL-induced activation of apoptosis effectors and particularly activation of caspase-8 and the executioner caspase-3, leading to increased poly-ADP-ribose polymerase cleavage and DNA fragmentation in prostate cancer cells. Furthermore, we showed that RG003 reduced COX-2 expression in cells. Previously, we showed that COX-2 was involved in resistance to an apoptosis mechanism; then, its inhibition by RG003 could render cells more sensitive to TRAIL treatment. We showed that nuclear factor-κB activation was inhibited after RG003 treatment. This inhibition was correlated with reduction in COX-2 expression and induction of apoptosis. Overall, we conclude, for the first time, that RG003 can enhance TRAIL-induced apoptosis in human prostate cancer cells. The significance of our in-vitro study with RG003 and TRAIL combined is very encouraging, suggesting the relevance of testing this combined treatment in xenograft animal models.

Novel methylsulfonyl chalcones as potential antiproliferative drugs for human prostate cancer: involvement of the intrinsic pathway of apoptosis.

Limited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. In the present study, the apoptotic mechanism of action of RG003 (2'-hydroxy-4-methylsulfonylchalcone) and RG005 (4'-chloro-2'-hydroxy-4-methylsulfonylchalcone) in association with intracellular signalling pathways was investigated in the hormone-independent prostate carcinoma cells PC-3 and DU145. We showed that these compounds induced apoptosis through the intrinsic pathway but not through the extrinsic one. We showed that synthetic chalcones induced an activation of caspase-9 but not caspase-8 in PC-3 cells. Even if both chalcones induced apoptosis in PC-3 cells, a dominant effect of RG003 treatment was observed resulting in a disruption of ∆ψm, caspase-9 and caspase-3 activation, PARP cleavage and DNA fragmentation. Furthermore, in regard to our results, it is clear that the simultaneous inhibition of Akt and NF-κB signalling can significantly contribute to the anticancer effects of RG003 and RG005 in PC-3 prostate cancer cells. NF-κB inhibition was correlated with the reduction of COX-2 expression and induction of apoptosis. Our results clearly indicate for the first time that RG003 and RG005 exert their potent anti­proliferative and pro-apoptotic effects through the modulation of Akt/NF-κB/COX-2 signal transduction pathways in PC-3 prostate cancer cells with a dominant effect for RG003.

Lead optimization of 4-imidazolylflavans: new promising aromatase inhibitors.

Our previous studies have shown that several 7-substituted-4-imidazolylflavans are potent inhibitors of aromatase. These compounds were designed considering the anti-aromatase effect of some natural flavonoids and the importance of an azole ring for synthetic inhibitors such as letrozole or anastrozole towards binding to the heme iron of aromatase. In this study, we report the optimization of these lead compounds by the modulation of flavan A ring. The resulting 7,8-benzo-4-imidazolylflavans were tested in order to assess their ability to inhibit aromatase. Biological data concerning enantiomers obtained from the chiral separation of the racemate compound 4-imidazolyl-7-methoxyflavan are also presented.

Structure and remodelling of the human parietal bone: an age and gender histomorphometric study.

OBJECTIVE: Despite its clinical usefulness, the internal structure and remodelling of parietal bone remained poorly documented. The aim of this study was to gain reliable information on parietal bone remodelling in living humans. MATERIALS AND METHODS: This study provided a site-specific analysis of static indices of turnover in relation to gender and age by using leftovers of parietal bone sampled in 100 patients (78 females; 22 males, aged 16-79 years). RESULTS: The bone architecture, cortical thickness, trabecular volume and cortical volume (C.Th, BV/TV, BV/CV) did not vary with gender. The number of osteoclasts (N.Oc/BPm) and the resorption surface (Oc.S/BS) were higher in females (p<0.05) when osteoclast resorbing activity did not vary with gender. Bone formation, osteoid surface (OS/BS) and surface covered by alkaline phosphatase-positive osteogenic cells (ALPS/BS) were higher in females (p<0.05 and p<0.01 respectively). All these parameters remained stable with aging. The osteocytic parameters, number of osteocytes (Ot.N/B.Ar) and number of osteocyte lacunae (T.L.N/B.Ar) were higher in females (p<0.05) and decreased with age in both genders (p<0.01). CONCLUSION: This study highlights the low and stable remodelling in the parietal bone. It appears to be higher in women. This stability probably reflects the low mechanical strains applied to the skull, particularly to the parietal bone.

Fabrication of porous substrates: a review of processes using pore forming agents in the biomaterial field.

This paper is a review of solid and casting manufacturing processes able to create porous materials, mainly in the biomaterial field. The considered methods are based on pore forming agents that are removed either by heating or by dissolution. All techniques lead to products presenting pores with amount, size, and shape are close to those of the initial pore formers. Porosities up to 90% with pores ranging from 1 to 2000 microm are reported. Major differences concern macrointerconnections that are more frequently obtained using foams, or porogens which undergo a melting stage during firing. Casting methods combined with solid free form fabrication are promising for the design of porous network through the manufacturing of 3D scaffolds corresponding to the desired porosity.

New 7,8-benzoflavanones as potent aromatase inhibitors: synthesis and biological evaluation.

Some natural compounds such as flavonoids are known to possess a moderate inhibitory activity against aromatase, this enzyme being an interesting target for hormone-dependent breast cancer treatment. It has been demonstrated that the modulation of flavonoid skeleton could increase anti-aromatase effect. Therefore, new 7,8-benzoflavanones were synthesized and tested for their activity toward aromatase inhibition. It was observed that the introduction of a benzo ring at position C-7 and C-8 on flavanone skeleton led to new potent aromatase inhibitors, the resulting 7,8-benzoflavanones being until nine times more potent than aminogluthetimide (the first aromatase inhibitor used clinically).

Synthesis and biological evaluation of 4-imidazolylflavans as nonsteroidal aromatase inhibitors.

A series of 4-imidazolylflavans having a variety of substituents on the 2-phenyl ring was synthesized and investigated for their inhibitory effect against aromatase. Structure-activity relationships of these compounds were determined. An additional chlorine atom or a cyano group at the 4' position did not enhance aromatase inhibition as well as a 3'-hydroxyl group. The influence of an additional 4'-hydroxyl group depends on the substitution pattern of A ring. Among these molecules, 4'-hydroxy-4-imidazolyl-7-methoxyflavan is only 2.2-fold less active than the letrozole (as assessed by IC50 values). Letrozole is used as the first-line therapy for metastatic breast cancer.

Synthesis and evaluation of 4-triazolylflavans as new aromatase inhibitors.

Aromatase is a target of pharmacological interest for the treatment of estrogen-dependent cancers. Azole derivatives such as letrozole or anastrozole have been developed for aromatase inhibition and are used for the treatment of breast tumors. In this paper, four 4-triazolylflavans were synthesized and were found to exhibit moderate to high inhibitory activity against aromatase.

Design, synthesis and evaluation of 4-imidazolylflavans as new leads for aromatase inhibition.

Two 4-imidazolylflavans were synthesized and their relative stereochemistry was established by 1H and 13C NMR data. These compounds were tested for their activity to inhibit aromatase. It was observed that the introduction of an imidazolyl group at carbon 4 on flavan nucleus led to potent molecules.

Synthesis and aromatase inhibitory activity of flavanones.

PURPOSE: Aromatase inhibitors are known to prevent the conversion of androgens to estrogens and play a significant role in the treatment of estrogen dependent diseases such as breast cancer. Some flavonoids have been reported as potent aromatase inhibitors; therefore, in an effort to develop novel anti breast cancer agents, B ring substituted flavanones with a 7-methoxy group on A ring were synthesized and tested to assess their ability to inhibit aromatase activity and to determine the optimal B ring substitution pattern. METHODS: A series of flavanones was prepared by cyclisation of 2'-hydroxychalcones previously obtained by Claisen-Schmidt condensation and the aromatase inhibitory activity of these compounds was investigated using human placental microsomes and radiolabeled [1,2,6,7-(3)H]-androstenedione as substrate. RESULTS: Almost all flavanones exhibited inhibitory effect on the aromatase activity but their potency was dependent on their B ring substitution pattern. Hydroxylation at position 3' and/or 4' enhanced the anti-aromatase activity; thus, 3',4'-dihydroxy-7-methoxyflavanone was found to be twice more potent than aminoglutethimide, the first aromatase inhibitor clinically used. CONCLUSIONS: These results indicated that these flavanones could be considered as potential anti breast cancer agents through the inhibition of aromatase activity and allowed us to select some of these compounds as skeleton for the development of flavonoid structurally-related aromatase inhibitors.

New aromatase inhibitors. Synthesis and inhibitory activity of pyridinyl-substituted flavanone derivatives.

Two (E)-pyridinyl-substituted flavanone derivatives were synthesized and UV irradiation of these compounds afforded a Z-enriched mixture. These products were tested for their ability to inhibit the cytochrome P450 aromatase. It was observed that the introduction of a pyridinylmethylene group at carbon 3 on flavanone nucleus led to a significant increase of aromatase inhibitory effect. Moreover, configuration had a substantial influence on the aromatase inhibitory activity since (E)-isomers were found to be more active than (Z)-isomers.