Javad Sharifi‐Rad

Isotretinoin as a Multifunctional Anticancer Agent: Molecular Mechanisms, Pharmacological Insights and Therapeutic Potential

ABSTRACT Despite notable advancements in conventional cancer therapies, challenges such as drug resistance, adverse effects, and high treatment costs remain significant obstacles. This situation calls for exploring new therapeutic options. One promising approach is drug repurposing, which uses existing medications with known effects to identify new anticancer agents. Isotretinoin (13‐ cis ‐retinoic acid), a vitamin A derivative typically used to treat severe acne, shows considerable potential as an anticancer agent. Recent studies suggest that isotretinoin has the potential to enhance the efficacy of cancer treatment and contribute to cancer inhibition by targeting specific molecular pathways. This review explores isotretinoin's chemistry, pharmacokinetics, and toxicity, emphasizing its role in cancer treatment through clinical and preclinical studies while elucidating its anticancer mechanisms. Both preclinical and clinical studies have revealed that isotretinoin can effectively inhibit the growth of tumor cells, induce apoptosis, and help regulate cellular differentiation in a range of cancers, including neuroblastoma, glioblastoma, breast, skin, lung, ovarian, cervical, and head and neck cancers. Isotretinoin works against cancer through several mechanisms. It activates retinoic acid receptors (RARs), suppresses oncogenic signaling pathways, and influences gene transcription related to cell cycle control and apoptosis. Moreover, combining isotretinoin with other treatments, like interferon‐alpha, chemotherapy drugs, or other targeted inhibitors, can create synergistic effects that improve treatment effectiveness and potentially lessen side effects. Although isotretinoin holds great promise, we still need more research to address its limitations, such as its toxicity, risks during pregnancy, and differing responses in various cancer types. Current research focuses on optimizing isotretinoin‐based therapies by refining dosage regimens to maximize efficacy and enhancing formulation strategies for improved absorption and reduced side effects. Ultimately, the use of isotretinoin in cancer treatment demonstrates the potential of repurposing established drugs and paves the way for more accessible and cost‐effective cancer therapies.

Piperine: an emerging biofactor with anticancer efficacy and therapeutic potential

Abstract Anticancer drug discovery needs serious attention to overcome the high mortality rate caused by cancer. There are still many obstacles to treating this disease, such as the high cost of chemotherapeutic drugs, the resulting side effects from the drug, and the occurrence of multidrug resistance. Herbaceous plants are a reservoir of natural compounds that can be anticancer drugs with novel mechanisms of action. Piperine, a bioactive compound derived from Piper species, is gaining attention due to its unique dual role in directly inhibiting tumor growth and enhancing the bioavailability of chemotherapeutic drugs. Unlike conventional treatments, Piperine exhibits a novel mechanism of action by modulating multiple signaling pathways, including apoptosis and autophagy, with low toxicity. Additionally, Piperine acts as a bioenhancer by improving the absorption and effectiveness of other anticancer agents, reducing the required dosage, and minimizing side effects. Therefore, this review aims to visualize a summary of Piperine sources, phytochemistry, chemical structure–anticancer activity relationship, anticancer activities of semi‐synthetic derivatives, pharmacokinetic and bioavailability, in vitro and in vivo preclinical studies, mechanism of antitumor action, human clinical trials, toxicity, side effects, and safety of Piperine. References were collected from the Pubmed/MedLine database ( https://pubmed.ncbi.nlm.nih.gov/ ) with the following keywords: “Piperine anticancer,” “Piperine derivatives,” “Piperine antitumor mechanism” and “Piperine pharmacokinetic and bioavailability,” after filter process by inclusion and exclusion criteria, 101 were selected from 444 articles. From 2013 to 2023, there were numerous studies regarding preclinical studies of Piperine of various cell lines, including breast cancer, prostate cancer, lung cancer, melanoma, cervical cancer, gastric cancer, osteosarcoma, colon cancer, hepatocellular carcinoma, ovarian cancer, leukemia, colorectal cancer, and hypopharyngeal carcinoma. In vivo, the anticancer study has also been conducted on some animal models, such as Ehrlich carcinoma‐bearing mice, Ehrlich ascites carcinoma cells‐bearing Balbc mice, hepatocellular carcinoma‐bearing Wistar rat, A375SM cells‐bearing mice, A375P cells‐bearing mice, SNU‐16 cells‐bearing BalbC mice, and HGC‐27‐bearing baby mice. Treatment with this compound leads to cell proliferation inhibition and induction of apoptosis. Piperine has been used for clinical trials of diseases, but no cancer patient report exists. Various semi‐synthetic derivatives of Piperine show efficacy as an anticancer drug across multiple cell lines. Piperine shows promise for use in cancer clinical trials, either as a standalone treatment or as a bioenhancer. Its bioenhancer properties may enhance the efficacy of existing chemotherapeutic agents, providing a valuable foundation for developing new anticancer therapies.

Anticancer activity and other biomedical properties of β‐sitosterol: Bridging phytochemistry and current pharmacological evidence for future translational approaches

AbstractSterols, including β‐sitosterol, are essential components of cellular membranes in both plant and animal cells. Despite being a major phytosterol in various plant materials, comprehensive scientific knowledge regarding the properties of β‐sitosterol and its potential applications is essential for scholarly pursuits and utilization purposes. β‐sitosterol shares similar chemical characteristics with cholesterol and exhibits several pharmacological activities without major toxicity. This study aims to bridge the gap between phytochemistry and current pharmacological evidence of β‐sitosterol, focusing on its anticancer activity and other biomedical properties. The goal is to provide a comprehensive understanding of β‐sitosterol's potential for future translational approaches. A thorough examination of the literature was conducted to gather relevant information on the biological properties of β‐sitosterol, particularly its anticancer therapeutic potential. Various databases were searched, including PubMed/MedLine, Scopus, Google Scholar, and Web of Science using appropriate keywords. Studies investigating the effects of β‐sitosterol on different types of cancer were analyzed, focusing on mechanisms of action, pharmacological screening, and chemosensitizing properties. Modern pharmacological screening studies have revealed the potential anticancer therapeutic properties of β‐sitosterol against various types of cancer, including leukemia, lung, stomach, breast, colon, ovarian, and prostate cancer. β‐sitosterol has demonstrated chemosensitizing effects on cancer cells, interfering with multiple cell signaling pathways involved in proliferation, cell cycle arrest, apoptosis, survival, metastasis invasion, angiogenesis, and inflammation. Structural derivatives of β‐sitosterol have also shown anti‐cancer effects. However, research in the field of drug delivery and the detailed mode of action of β‐sitosterol‐mediated anticancer activities remains limited. β‐sitosterol, as a non‐toxic compound with significant pharmacological potential, exhibits promising anticancer effects against various cancer types. Despite being relatively less potent than conventional cancer chemotherapeutics, β‐sitosterol holds potential as a safe and effective nutraceutical against cancer. Further comprehensive studies are recommended to explore the biological properties of β‐sitosterol, including its mode of action, and develop novel formulations for its potential use in cancer treatment. This review provides a foundation for future investigations and highlights the need for further research on β‐sitosterol as a potent superfood in combating cancer.