Prospects for Prostate Cancer Chemotherapy: Cytotoxic Evaluation and Mechanistic Insights of Quinolinequinones with ADME/PK Profile.

The evaluation of in vitro biological activity of several previously reported quinolinequinones (AQQ1-5) against 60 human cancer cell lines (NCI-60) used by the National Cancer Institute's Developmental Therapeutics Program (DTP) contributed to our earlier research on possible anticancer and/or antibacterial agents. Of interest, NCI-60 screening revealed that two quinolinequinones (AQQ1 and AQQ2) significantly reduced the proliferation of several cancer genotypes. Following the administration of a single dose and five additional doses, all quinolinequinones demonstrated a significant inhibitory effect on the growth of leukemia and other cancer cell lines. Hence, a series of subsequent in vitro biological assessments were performed to further understand the mechanistic impact of the compounds. In MTT assays, it was found that AQQ1 and AQQ2 exhibited higher efficacy against DU-145 cells (IC50 4.18 µM and 4.17 µM, respectively) compared to MDA-MB-231 (IC50 8.27 and 13.33 µM, respectively) and HCT-116 cells (IC50 5.83 and 9.18 µM, respectively). Additionally, AQQ1 demonstrated greater activity in this context. Further investigations revealed that AQQ1 inhibited DU-145 cell growth and migration dose-dependently. Remarkably, arrest of the DU-145 cell cycle at G0/G1 phase and ROS elevation were observed. Pharmacokinetic (PK) studies revealed that AQQ1 has better PK parameters than AQQ2 with %F of 9.83 in rat. Considering the data obtained with human liver microsomal stability studies, AQQ1 should have a better PK profile in human subjects. In silico studies (molecular dynamics) with three kinases (CDK2, CDK4, and MAPK) leading to cell cycle arrest at G0/G1 identified MAPK as a probable target for AQQ1. Taken together, our results showed that AQQ1 could be a potential chemotherapeutic lead molecule for prostate cancer.

Efficacy of hypochlorous acid as an alternative oral antimicrobial agent on human gingival fibroblasts, Aggregatibacter actinomycetemcomitans, and Candida albicans biofilms in vitro.

This study compared the cytotoxicity and antimicrobial activity of hypochlorous acid (HOCl) at 50 ppm and 200 ppm and 0.2% chlorhexidine (CHX) at various time intervals, in vitro. Cell viability and cytotoxicity of human gingival fibroblasts (HGF) were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and the lactate dehydrogenase assay. Antimicrobial effects on Aggregatibacter actinomycetemcomitans and Candida albicans were determined using the time-kill method. All solutions exhibited a significant impact on HGFs in a dose- and time-dependent manner. 50 ppm HOCl demonstrated the highest cell viability, followed by 200 ppm HOCl. Both HOCl solutions were less cytotoxic to HGFs than 0.2% CHX. 50 ppm and 200 ppm HOCl demonstrated stronger efficiencies than CHX against A. actinomycetemcomitans and C. albicans. The data suggest that HOCl solutions have potential as an alternative antiseptic to CHX due to their lower cytotoxicity and superior antimicrobial activity, but optimal dosage of HOCl requires further investigations.

Cytotoxic activity of quinolinequinones in cancer: In vitro studies, molecular docking, and ADME/PK profiling.

Lead molecules containing 1,4-quinone moiety are intriguing novel compounds that can be utilized to treat cancer owing to their antiproliferative activities. Nine previously reported quinolinequinones (AQQ1-9) were studied to better understand their inhibitory profile to produce potent and possibly safe lead molecules. The National Cancer Institute (NCI) of Bethesda chose all quinolinequinones (AQQ1-9) based on the NCI Developmental Therapeutics Program and tested them against a panel of 60 cancer cell lines. At a single dose and five further doses, AQQ7 significantly inhibited the proliferation of all leukemia cell lines and some breast cancer cell lines. We investigated the in vitro cytotoxic activities of the most promising compounds, AQQ2 and AQQ7, in MCF7 and T-47D breast cancer cells, DU-145 prostate cancer cells, HCT-116 and COLO 205 colon cancer cell lines, and HaCaT human keratinocytes using the MTT assay. AQQ7 showed particularly high cytotoxicity against MCF7 cells. Further analysis showed that AQQ7 exhibits anticancer activity through the induction of apoptosis without causing cell cycle arrest or oxidative stress. Molecular docking simulations for AQQ2 and AQQ7 were conducted against the COX, PTEN, and EGFR proteins, which are commonly overexpressed in breast, cervical, and prostate cancers. The in vitro ADME and in vivo PK profiling of these compounds have also been reported.

Analysis of Quinolinequinone Analogs with Promising Cytotoxic Activity against Breast Cancer.

It is quite challenging to find out bioactive molecules in the vast chemical universe. Quinone moiety is a unique structure with a variety of biological properties, particularly in the treatment of cancer. In an effort to develop potent and secure antiproliferative lead compounds, five quinolinequinones (AQQ1-5) described previously have been selected and submitted to the National Cancer Institute (NCI) of Bethesda to envisage their antiproliferative profile based on the NCI Developmental Therapeutics Program. According to the preliminary in vitro single-dose anticancer screening, four of five quinolinequinones (AQQ2-5) were selected for five-dose screening and they displayed promising antiproliferative effects against several cancer types. All AQQs showed a excellent anticancer profile with low micromolar GI50 and TGI values against all leukemia cell lines, some non-small cell lung and ovarian cancer, most colon, melanoma, and renal cancer, and in addition to some breast cancer cell lines. AQQ2-5 reduced the proliferation of all leukemia cell lines at a single dose and five additional doses, as well as some non-small cell lung and ovarian cancer, the majority of colon cancer, melanoma and renal cancer, and some breast cancer cell lines. This motivated us to use in vitro, in silico, and in vivo technologies to further investigate their mode of action. We investigated the in vitro cytotoxic activities of the most promising compounds, AQQ2 and AQQ3, in HCT-116 colon cancer, MCF7 and T-47D breast cancer, and DU-145 prostate cancer cell lines, and HaCaT human keratinocytes. Concomitantly, IC50 values of AQQ2 and AAQ3 against MCF7 and T-47D cell lines of breast cancer, DU-145 cell lines of prostate cancer, HCT-116 cell lines of colon cancer, and HaCaT human keratinocytes were determined. AQQ2 exhibited anticancer activity through the induction of apoptosis and caused alterations in the cell cycle. In silico pharmacokinetic studies of all analogs have been carried out against ATR, CHK1, WEE1, CDK1, and CDK2. In addition to this, in vitro ADME and in vivo pharmacokinetic profiling for the most effective AAQ (AAQ2) have been studied.

Ubiquitin proteasomal system is a potential target of the toxic effects of organophosphorus flame retardant triphenyl phosphate.

The consumption of the widely used flame retardant Triphenyl phosphate (TPP) is increasing. It is now frequently detected in the environment and also domestically. Although the possibility of dermal exposure to TPP is quite high, little is known about its potential molecular toxicity mechanisms. In this study, we found that TPP caused cytotoxicity on human skin keratinocytes (HaCaT) and significantly inhibited the proliferation and cell migration in a concentration-dependent manner. Additionally, HaCaT cells were sensitive to TPP-induced apoptosis. Reactive oxygen species production was induced with TPP, which increased the protein carbonylation and lipid peroxidation levels. Moreover, TPP inhibited proteasome activity and increased the accumulation of ubiquitinated proteins. Exposure to TPP significantly increased the HSP90, HSP70, GRP94 and GRP78 protein levels. Overall, our findings indicate that TPP may pose a risk to human health and contribute to the current understanding of the risks of TPP at the molecular level.

In Vitro and In Silico Study to Assess Toxic Mechanisms of Hybrid Molecules of Quinone-Benzocaine as Plastoquinone Analogues in Breast Cancer Cells.

We managed to obtain three different series of 2,3-dimethyl-1,4-benzoquinones, named nonhalogenated and halogenated (brominated and chlorinated) PQ analogues, via the molecular hybridization strategy. Sixteen of eighteen hybrid molecules were selected by the National Cancer Institute (NCI) of Bethesda for their in vitro antiproliferative potential against the full NCI 60 cell line panel. The hybrid molecules (BrPQ5, CIPQ1, and CIPQ3) showed good growth inhibition at 10 µM concentration, particularly against breast cancer cell lines. As per the results obtained from in vitro antiproliferative evaluation, cytotoxic activities of the hybrid molecules (BrPQ5, CIPQ1, and CIPQ3) were evaluated with an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in T47D and MCF7 breast cancer and human umbilical vein endothelial (HUVEC) cells. Molecules exhibited cytotoxic activity, and especially, CIPQ1 showed remarkable cytotoxic activity and good selectivity on T47D and MCF7 cells. Furthermore, CIPQ1 could inhibit cell proliferation, cause apoptotic cell death and disturb the cell cycle in T47D and MCF7 cells. Additionally, CIPQ1 caused oxidative stress induction in both cells, more so in T47D. In vitro study results indicated that the anticancer activity of CIPQ1 was more prominent in T47D cells than in MCF7 cells. The compound CIPQ1 showed a prominent binding with JNK3 in silico. Thus, the obtained hybrid molecules via the molecular hybridization strategy of two important pharmacophores could be useful in the discovery of novel antiproliferative agents, and CIPQ1 could be considered a promising drug candidate.

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction.

Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI's Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50 parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50 values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC50 values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.