Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Online First

As the number of new cancer cases increases every year, there is a necessity to develop new drugs for the treatment of different types of cancers. Plants' resources are considered to be huge reservoirs for therapeutic agents in nature. Among all the medicinal plants, Oroxylum indicum is one of the most widely used medicinal plants in India, China, and Southeast Asian countries. Combinatorial drug treatment, on the other hand, is favored over single drug treatment in order to target multiple biomolecular moieties that help in the growth and development of cancer. Therefore, combinatorial drug treatment using a co-crystal of multiple drugs gives researchers an idea of the development of a new type of drug for targeting multiple targets. In this study, a new co-crystal of chrysin and oroxylin A was isolated from the leaves of O. indicum, and its anticancer properties were studied in cervical cancer cells HeLa.

This study was conducted with the aim of identifying new anticancer compounds from the leaves of Oroxylum indicum and studying the anticancer properties of the isolated compound.

In this study, we elucidated the structure of a new co-crystal compound, which was isolated from the leaf extract of Oroxylum indicum. The apoptosis induction mechanism of the newly discovered co-crystal in HeLa cells was also studied.

A crystal compound from the chloroform extract of leaves of Oroxylum Indicum was isolated by solvent fractionation and chromatographic methods involving HPLC. The molecular structure of the isolated crystal was elucidated by Single Crystal-XRD, FT-IR analysis, and further determined by LC-MS. The antiproliferative activity was carried out using an MTT assay and fluorescence microscopy, and the mechanism of apoptosis was determined using Western blotting techniques.

The novel co-crystal consists of two active pharmaceutical ingredients (APIs) in a 1:1 ratio, i.e., oroxylin A and chrysin. The isolated new co-crystal induced death in HeLa cells with a very low IC50 value of 8.49µM. It induced caspase-dependent apoptosis in HeLa cells by activation of Caspase-3 through inhibition of ERKs and activation of p38 of MAPK cell signalling pathway.

This study presents the first report on the discovery of a naturally occurring co-crystal of chrysin and oroxylin A and the involvement of ERKs and p38 of MAPK pathways in the induction of apoptosis in HeLa cells by the co-crystal. Our study sheds light on the development of a co-crystal of chrysin and oroxylin A in a specific ratio of 1:1 for combination therapy of the two APIs. The purified co-crystal was found to be more efficient compared to the compounds present individually. Further analysis of the physiochemical properties and molecular mechanisms of the isolated co-crystal in different cancer cells is warranted for its application in therapeutics.

Phytochemicals have long remained an essential component of the traditional medicine system worldwide. Advancement of research in phytochemicals has led to the identification of novel constituents and metabolites from phytochemicals, performing various vital functions ranging from antimicrobial properties to anticarcinogenic roles.This plant is traditionally used by local people to manage inflammation. In this study, we aim to extract and chemically profile the essential oil from the leaves of Cleistocalyx operculatus (Roxb.) Merr. & Perry and study of the anti-inflammatory and anti-proliferative role of essential oil.

The hydro distillation method was used for the extraction of essential oil, and the GC-MS was applied for the chemical profiling. The percentage of cell viability was calculated using a crystal violet assay, colony formation assay was performed using Semiquantitative PCR, Propodium iodite staining was used for cell death assay, and Western blotting was used to determine antibodies and proteins. Schrodinger 2015 software was used for molecular docking.

Myrcene, a monoterpene, constitutes 56% of the oil and could be attributed to its anti-inflammatory potential. Treatment of LPS-challenged mouse macrophages RAW264.7 cells with essential oil resulted in a decline in the inflammatory markers, such as IL-1β, TNFα, iNOS, COX-2, and NFκB. Further, essential oil inhibited cancer PC-3, A431, A549, and MCF-7 cell lines at concentrations lower than normal PNT2 and HEK-293 cell lines. This decline in proliferative potential can be attributed to a decline in anti-apoptotic proteins, such as procaspase 3 and PARP, an increase in CKIs, such as p21, and a decline in the Akt signaling responsible for survival.

The essential oil of the plant Cleistocalyx operculatus may be a potential lead for anti-inflammatory and anti-proliferative function.

Gratiola officinalis L. (hedge hyssop), a medicinal plant of the Scrophulariaceae family, has diuretic, purgative, and vermifuge properties. It is used as a herbal tea to treat chronic gastroenteritis, renal colic, jaundice, and intestinal worms. Previously, we have found that an extract from G. officinalis is nontoxic and has antitumor, antioxidant, antimicrobial, antiinflammatory, anticachexic, and other properties. Our aims in this study were to separate the G. officinalis extract into individual fractions, to identify the most biologically active fractions, and to examine the chemical composition of these fractions and their biological activity toward A498 renal carcinoma cells.

The G. officinalis extract was fractionated by reversed-phase high-performance liquid chromatography, and each fraction was tested for antitumor activity. The active fractions were characterized by UV–visible electron spectral analysis, circular dichroism analysis, Fourier transform infrared spectroscopy, high-performance liquid chromatography, electrospray ionization tandem mass spectrometry, and nuclear magnetic resonance spectroscopy.

Two antitumor-active fractions of a flavonoid nature were isolated and chromatographically purified. On the basis of the nuclear magnetic resonance data, the aglycone fragment of the main component of one fraction was found to be structured as 2-(3,4-dimethoxyphenyl)-7-hydroxychroman-4-one, or 3',4'-dimethoxy-7-hydroxyflavanone.

The antitumor effect of the most active fraction containing 7-O-glucoside of apigenin, glycoside 7,3'-di-O-luteolin and trace amounts of eupatilin against renal carcinoma A498 cells was manifested in its cytotoxic, cytostatic, apoptotic and autophagosomal activities. In addition, we found 3-(1-2)-glucoside of soyaspogenol B, which is a pentacyclic triterpenoid in the structure.

One of the growing diseases in today's human societies is cancer, which has become a major challenge, especially in industrialized and developing countries. Cancer treatments are diverse, but they usually use surgery, chemotherapy, and radiotherapy to improve patients. Existing drugs are usually expensive and, in some cases, are not effective due to drug resistance and side effects. Finding compounds of natural origin can be somewhat effective and useful in helping doctors to treat this disease. Ferula plants, which are traditionally used as spices or for medicinal purposes, can be a good source for finding anti-cancer compounds due to their various compounds, such as monoterpenes, sulfide compounds, and polyphenols. Several studies have shown that compounds found in Ferula plants have significant anticancer effects on various types of cancer cells.

This article was compiled with the aim of collecting evidence and articles related to the anti-cancer effects of three compounds obtained from these plants, namely Conferone, Diversin, and Ferutinin.

This review article was prepared by searching the terms Conferone, Diversin, Ferutinin and cancer and related information was collected through searching electronic databases such as ISI Web of Knowledge, PubMed and Google Scholar until the March of 2024.

The results of this review showed that relatively comprehensive studies have been conducted in this field and these studies have shown that these compounds can be used in the design of future anticancer drugs. Among the examined compounds, conferone showed that it has the best effect on cancer cells.

Deaths from cancer are still very common all over the world and continue to be the focus of scientific research. Chemotherapy is one of the primary treatments used to prevent deaths from cancer. Side effects of chemotherapeutic drugs and resistance of cells to drugs are essential problems that limit the treatment process. Drug combination therapy is regarded as a significant application that inhibits the growth of tumors and is anticipated to provide a solution for the issues encountered. The combination therapy aims at a synergistic effect that will limit drug resistance and cytotoxic effects with appropriate drug combinations. In this context, we aim to investigate the in vitro, in vivo, and in silico effects of single and combined doses of umbelliferone and irinotecan, known for their anticarcinogenic and curative effects, on MDA-MB-231 breast cancer cell lines and the model organism Drosophila melanogaster.

Irinotecan is currently used as an anticarcinogenic drug. Anticarcinogenic effects of umbelliferone have also been detected. The in vivo, in vitro, and in silico impacts of single and combined doses use of these two agents are not yet available in the literature.

This study aims to determine the anticarcinogenic effects of single and combined use of umbelliferone and irinotecan at the molecular level. It also attempts to determine the binding energies of chemicals to cancer-related proteins through docking and molecular dynamic studies.

The cytotoxic effects of individual and combinational doses of umbelliferone and irinotecan on the MDA-MB-231 cell line and D. melanogaster were calculated by XTT and probit analyses. IC50 values for the cancer cells, LC50, and LC99 values for D. melanogaster were found. Gene expression analysis was performed to determine the effects of chemical agents on miR-7, miR-11, and miR-14, and their expression levels were found. The sequences of miRNAs not found in the literature were determined, and their molecular imaging was performed. In addition, the binding energies of irinotecan and umbelliferone to Bcl-2, Bad, and Akt1 proteins, which are known to have apoptotic effects, were found by the molecular docking method. Molecular dynamics studies of Bad proteins and chemicals were also performed. The drug potential of chemicals was determined by ADME/T analysis.

The cytotoxic effect on cells was calculated, and the IC50 value of umbelliferone was calculated as 158 µM, the IC50 value of irinotecan was calculated as 48,3 µM and the IC50 value was calculated as 20 µM. In the probit analysis performed to calculate the cytotoxic effects of drugs on D. melanogaster, the LC50 value of umbelliferone was 2,5 µM, and the LC99 value was 13,4 µM. The LC50 value of irinotecan was found to be 0,1 µM, and the LC99 value was 0,28 µM. It was concluded that single and combined doses of chemicals in the invasion experiment significantly affected the spread of cells. As a result of expression analysis, a significant increase in Hsa-miR-7 (Homo sapiens miRNA-7), Hsa-miR-14 (Homo sapiens miRNA-14), and Hsa-miR-11(Homo sapiens miRNA-11) expression was observed in cells treated with umbelliferone irinotecan compared to the control groups.

In our study, it can be concluded that the cytotoxic effects of individual and combination doses of umbelliferone and irinotecan on MDA-MB-231 cells and D. melanogaster larvae are significant. In addition, the effects of umbelliferone and irinotecan on the expression level of miR-7, which is a common D. melanogaster and human miRNA, should be widely investigated. Expression analyses and docking studies of Hsa-miR-11 and Hsa-miR-14, which have been newly studied and are not in data repositories, are important for cancer research. In particular, the expression and binding energy of these miRNAs in new drug combinations and the expression level in different cancer cell lines are important for future studies. Another crucial point is that in vivo tests using different model species validate the usage of drugs at both single and mixed dosages.

As a result of this study, the in vivo, in vitro, and in silico effects of single and combined doses of umbelliferone and irinotecan were determined. In future studies, it would be useful to determine the binding energies of umbelliferone and irinotecan to other cancer-related proteins and to find their interactions with different miRNAs. Additionally, studies on different model organisms are also important.

Mesoionic compound MI-D possesses important biological activities, such as anti-inflammatory and antitumoral against melanoma and hepatocarcinoma. Glioblastoma is the most aggressive and common central nervous system tumor in adults. Currently, chemotherapies are not entirely effective, and the survival of patients diagnosed with glioblastoma is extremely short.

In this study, we aimed to evaluate the cytotoxicity of MI-D in noninvasive A172 glioblastoma cells and establish which changes in functions linked to energy provision are associated with this effect.

Cells A172 were cultured under glycolysis and phosphorylation oxidative conditions and evaluated: viability by the MTT method, oxygen consumption by high-resolution respirometry, levels of pyruvate, lactate, citrate, and ATP, and glutaminase and citrate synthase activities by spectrophotometric methods.

Under glycolysis-dependent conditions, MI-D caused significant cytotoxic effects with impaired cell respiration, reducing the maximal capacity of the electron transport chain. However, A172 cells were more susceptible to MI-D effects under oxidative phosphorylation-dependent conditions. At the IC25, inhibition of basal and maximal respiration of A172 cells was observed, without stimulation of the glycolytic pathway or Krebs cycle, along with inhibition of the activity of glutaminase enzyme, resulting in a 30% ATP deficit. Additionally, independent of metabolic conditions, MI-D treatment induced cell death in A172 cells by apoptosis machinery/processes.

The impairment of mitochondrial respiration by MI-D under the condition sustained by oxidative phosphorylation may enhance the cytotoxic effect on A172 glioma cells, although the mechanism of cell death relies on apoptosis.