Evidence-based capacity of natural cytochrome enzyme inhibitors to increase the effectivity of antineoplastic drugs

Abstract

Cytochrome (CYP) enzymes catalyze the metabolism of numerous exogenous and endogenous substrates in cancer therapy leading to significant drug interactions due to their metabolizing effect. CYP enzymes play an important role in the metabolism of essential anticancer medications. They are shown to be overexpressed in tumor cells at numerous locations in the body. This overexpression could be a result of lifestyle factors, presence of hereditary variants of CYP (Bio individuality) and multi-drug resistance. This finding has sparked an interest in using CYP inhibitors to lower their metabolizing activity as a result facilitating anti-cancer medications to have a therapeutic impact. As a result of the cytotoxic nature of synthetic enzyme inhibitors and the increased prevalence of herbal medication, natural CYP inhibitors have been identified as an excellent way to inhibit overexpression sighting their tendency to show less cytotoxicity, lesser adverse drug reactions and enhanced bioavailability. Nonetheless, their effect of lowering the hindrance caused in chemotherapy due to CYP enzymes remains unexploited to its fullest. It has been observed that there is a substantial decrease in first pass metabolism and increase in intestinal absorption of chemotherapeutic drugs like paclitaxel when administered along with flavonoids which help suppress certain specific cytochrome enzymes which play a role in paclitaxel metabolism. This review elaborates on the role and scope of phytochemicals in primary, secondary and tertiary care and how targeted prevention of cancer could be a breakthrough in the field of chemotherapy and oncology. This opens up a whole new area of research for delivery of these natural inhibitors along with anticancer drugs with the help of liposomes, micelles, nanoparticles, the usage of liquid biopsy analysis, artificial intelligence in medicine, risk assessment tools, multi-omics and multi-parametric analysis. Further, the site of action, mechanisms, metabolites involved, experimental models, doses and observations of two natural compounds, quercetin & thymoquinone, and two plant extracts, liquorice & garlic on CYP enzymes have been summarized. Graphical Abstract

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity

“…Many of the CYPs long considered orphan CYPs (e.g., CYP2U1, 2S1, and 4V2) have been implicated in cancer and several other diseases [ 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ]. Major drug-metabolizing CYPs, such as 1A2, 2D6, 2C9, and 3A4, are implicated in detrimental effects by bioactivation of substances to toxic metabolites [ 100 ], drug–drug or herb–drug interactions [ 101 , 102 , 103 ], and chemoresistance [ 104 , 105 ]. This extensive impact urges a comprehensive assessment of all manners of CYP activity modulation, not only of expression regulation, the influence of non-synonymous mutations, or direct inhibition by chemical compounds, but additionally those of PPIs that may modulate CYP activity.…”

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

“…However, endocrine resistance is still a problem, with onethird of women reporting recurrence within 15 years of taking Tamoxifen 14 . Additionally, comprehending the complex relationship between CYP2D6 activity in Wnt signaling and the effect of vitamin D3 on endoxifen levels can offer important insights towards overcoming drug resistance in ER Positive breast tumors [15][16][17] . Furthermore, an array of strategies, including NOTCH targeted therapy and an understanding of various ligand-receptor interactions, functions of NOTCH signaling in breast cancer sensitivity can be used to clarify the processes of NOTCH signaling 18,19 .…”

Aldo-keto reductases: Role in cancer development and theranostics

“…CYPs as well as AKRs that play a critical role in regulating the efficacy of drugs are also implicated in chemoresistance [ 8 , 9 ]. Inhibitors of CYPs and AKRs have therefore emerged as attractive candidate agents for cancer therapy and to counter chemoresistance [ 10 ].…”