In silico-based identification of phytochemicals as novel human phosphoglycerate mutase 1 (PGAM1) inhibitors for cancer therapy.

Targeting cancer-specific metabolic and mitochondrial remodeling has emerged as a novel and selective strategy for cancer therapy during recent years. Phosphoglycerate Mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate and plays a critical role in cancer progression by coordinating glycolysis and biosynthesis. PGAM1 has been reported to be over expressed in a variety of cancer types and its inhibition results in decreased tumor growth and metastasis. Recently, there has been a growing interest in identification and characterization of novel PGAM1 inhibitors for the treatment of cancer. In the current study, in silico tools were used to find out natural inhibitors of PGAM1. For docking studies, a database of 5006 phytochemicals were docked against PGAM1, using MOE software in order to identify the compounds which show better binding affinities than PGMI-004A. Out of 5006 compounds screened, eight compounds (1,3-cyclopentanedione, glyflavanone B, 6-demethoxytangeretin, gnaphaliin, lantalucratin A and -(-) morelensin, abyssinin II and monotesone-A) showed significant binding affinity with PGAMI active site. Further, the eight selected compounds were evaluated for different pharmacokinetics parameters using admetSAR, the obtained results demonstrated that none of these hit compounds violated Lipinski's drug rule of 5 and all the hit compounds possess favorable ADMET properties. This study has unveiled the potential of phytochemicals that could serve as probable lead candidates for the development of PGAM1 inhibitors as anti-cancer agents.

Germacrone: A Potent Secondary Metabolite with Therapeutic Potential in Metabolic Diseases, Cancer and Viral Infections.

Natural products, an infinite reserve of bioactive molecules, will continue to serve humans as an important source of therapeutic agents. Germacrone is a bioactive natural compound found in the traditional medicinal plants of family Zingiberaceae. This multifaceted chemical entity has become a point of focus during recent years due to its numerous pharmacological applications, e.g., anticancer, anti-inflammatory, antiviral, antioxidant, anti-adipogenic, anti-androgenic, antimicrobial, insecticidal, and neuroprotective. Germacrone is an effective inducer of cell cycle arrest and apoptosis in various cancers (breast, brain, liver, skin, prostate, gastric, and esophageal) via modulation of different cell signaling molecules and pathways involved in cancer proliferation. This is the first report highlighting the wide spectrum of pharmacological activities exhibited by germacrone. The reported data collected from various shreds of evidences recommend that this multifaceted compound could serve as a potential drug candidate in the near future.

Oleandrin: A bioactive phytochemical and potential cancer killer via multiple cellular signaling pathways.

Nerium oleander, a member of family Apocynaceae, is commonly known as Kaner in various countries of Asia and Mediterranean region. This plant has been renowned to possess significant therapeutic potential due to its various bioactive compounds which have been isolated from this plant e.g., cardiac glycosides, oleandrin, α-tocopherol, digitoxingenin, urosolic acid, quercetin, odorosides, and adigoside. Oleandrin, a saponin glycoside is one of the most potent and pharmacologically active phytochemicals of N. oleander. Its remarkable pharmacotherapeutic potential have been interpreted as anticancer, anti-inflammatory, anti-HIV, neuroprotective, antimicrobial and antioxidant. This particular bioactive entity is known to target the multiple deregulated signaling cascades of cancer such as NF-κB, MAPK, and PI3K/Akt. The main focus of the current study is to comprehend the action mechanisms of oleandrin against various pathological conditions. The current review is a comprehensive summary to facilitate the researchers to understand the pharmacological position of the oleandrin in the arena of drug discovery, representing this compound as a new drug candidate for further researches. Moreover, in vivo and in silico based studies are required to explore the mechanistic approaches regarding the pharmacokinetics and biosafety profiling of this compound to completely track its candidature status in natural drug discovery.

Effects of glutathione-S-transferase polymorphisms on the risk of breast cancer: a population-based case-control study in Pakistan.

Cancer is widely accepted as one of the major health issues. Diet composition and exposure to environmental genotoxic and carcinogenic agents such as polycyclic aromatic hydrocarbons (PAHs) are among the causative factors for various types of cancers, including breast cancer. Low penetrance genes including glutathione S transferases (GST) in association with environmental factors can contribute greatly in the development of breast cancer. We were interested to investigate the association of the polymorphisms of GSTM1, GSTT1, GSTP1 and GSTO2 with the risk of breast cancer in the Pakistani population. One hundred women visiting the Department of Radiology and Oncology, Nishter Hospital, Multan with pathologically confirmed breast cancer, and 100 healthy volunteers from central Pakistan were enrolled in the present study. The strength of the association of various factors with breast cancer was measured by calculating odd ratios (ORs) which were determined by logistic regression. All P values cited are two-sided; differences resulting in a P value of less or equal to 0.05 were declared statistically significant. The Hardy Weinberg equilibrium was tested for the genotype proportions in the control group, as a measure of quality control. Those aged 36-45, in menopause or with a history of cancer in the family had a significantly higher prevalence of breast cancer compared with controls. The frequency of GSTM1 and GSTT1 was similar in both control and patients suggesting no association with the risk of cancer development, however GSTM1 and GSTT1 were significantly linked with the risk of breast cancer in smokers and in women with a history of breast cancer in the family respectively. Similarly women homozygous for GSTP1 or GSTO2 and with a history of breast cancer, or in menopause, were at greater risk of breast cancer than wild type or heterozygotes. Our data suggest that genetic differences in some GST genes may be linked with an increased susceptibility to breast cancer. Furthermore it also gives an insight into the interaction between the GST polymorphisms and pre-menopausal diagnosis of breast cancer.