The multifaceted antineoplastic role of pyrimethamine against human malignancies

Abstract

Cancer accounted for nearly 10 million deaths in 2020 and is the second leading cause of death worldwide. The chemotherapeutic agents that are in clinical practice possess a broad range of severe adverse effects towards vital organs which emphasizes the importance of the discovery of new therapeutic agents or repurposing of existing drugs for the treatment of human cancers. Pyrimethamine is an antiparasitic drug used for the treatment of malaria and toxoplasmosis with a well‐documented excellent safety profile. In the last 5 years, numerous efforts have been made to explore the anticancer potential of pyrimethamine in in vitro and in vivo preclinical models and to repurpose it as an anticancer agent. The studies have demonstrated that pyrimethamine inhibits oncogenic proteins such as STAT3, NF‐κB, DX2, MAPK, DHFR, thymidine phosphorylase, telomerase, and many more in a different types of cancer models. Moreover, pyrimethamine has been reported to work in synergy with other anticancer agents, such as temozolomide, to induce apoptosis of tumor cells. Recently, the results of phase‐1/2 clinical trials demonstrated that pyrimethamine administration reduces the expression of STAT3 signature genes in tumor tissues of chronic lymphocytic leukemia patients with a good therapeutic response. In the present article, we have reviewed most of the published articles related to the antitumor effects of pyrimethamine in malignancies of breast, liver, lung, skin, ovary, prostate, pituitary, and leukemia in in vitro and in vivo settings. We have also discussed the pharmacokinetic profile and results of clinical trials obtained after pyrimethamine treatment. From these studies, we believe that pyrimethamine has the potential to be repurposed as an anticancer drug.

PKM2 Confers Purine Metabolic Advantage and Enhances Lenvatinib Resistance in Hepatocellular Carcinoma

“…Purine nucleotides are basic components of DNA and RNA in cellular biological process, thus impaired purine metabolism is associated with the regression of cancer [37]. In our present study, we provide a new insight into lenvatinib resistance contributed by purine metabolism pathway.…”

“…Numerous effects have been made to identify the anticancer potential of pyrimethamine in vitro and in vivo [37]. Therefore, PKM2 and DHFR are available targets and altering its expression levels or activity could provide promising outcomes in cancer therapy.…”

Escaping mechanisms of ESKAPE pathogens from antibiotics and their targeting by natural compounds

“…Beside, about 70% of these natural compounds have been extracted from actinomycetes (a group of Gram-positive mycelial bacteria) and merely 1% of actinomycetes have been cultured so far indicating the abundance of hidden bioactive compounds in the bacterial kingdom. It is highly essential to speed up the discovery of bioactive compounds from unexplored bacterial and plant sources 158 , 159 , 160 , 161 . Antibiotic discovery faces several constraints.…”

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

“…The thymidine synthetic pathway depends on the methylation of deoxyuridine, the methyl donor being methylenetetrahydrofolate [247][248][249][250]. The standard DHFR inhibitor used for over 50 years in cancer treatment has been MTX [251,252].…”