Synergistic combination of PMBA and 5-fluorouracil (5-FU) in targeting mutant KRAS in 2D and 3D colorectal cancer cells

Heliyon

Asmita Magotra¹  Syed Mohmad Shah²  Bhahwal Ali Shah³  Arem Qayum⁴  Shashank Kumar Singh⁵  Utpal Nandi⁵  P.R. Sharma⁶ 

[1] Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India;Corresponding author.;Technology of Kashmir, Srinagar, 190001, India;Cancer Pharmacology Division, Indian Institute of Integrative Medicine, CSIR, Jammu, 180001, India;PK-PD, Toxicology and Formulation Division, Indian Institute of Integrative Medicine, CSIR, Jammu, 180001, India;;Sher-e-Kashmir University of Agricultural Sciences &

关键词: Colon cancer;    PMBA;    5-fluorouracil;    KRAS;    Spheroid-formation (colonospheres);    Combination study;   

DOI  :  

来源: DOAJ

【 摘 要 】

β-Boswellic acid (β-BA), a potent NF-kB signaling pathway inhibitor, has shown synergistic anti-cancerous activity (NCT03149081, NCT00243022 and NCT02977936) in various clinical trials as complementary therapies. The study has been conducted to investigate the effect and efficacy of 2-pyridin-4-yl methylene β-boswellic acid (PMBA) and 5-Flourouracil (5-FU) in combination therapy for the treatment of KRAS mutant colon cancer. Analysis of isobologram showed synergistic combination index (CI > 1) of PMBA and 5-FU against the HCT-116G13D and SW-620G12V cell lines. The growth-inhibiting PMBA also caused apoptosis mediating effects with dose-dependent increase in caspase-3 activity, while inhibiting the formation of colonies in combination with 5-FU. As evident, PMBA affected colorectal 3D CSC properties including the ability to self-renew along with the expression of multi-drug resistance genes, viz., ABCB1, ABCC1 and ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and CSC markers like CD44, CD166, EPCAM, OCT-4, SOX-2, and NANOG compared with those in 2D model explaining the expression pattern of oncogenic KRASG13D, G12V mutation. When examined for plasma level of PMBA (20 mg) and PMBA+5-FU (20 + 40 mg), a time-dependent increase in the level of the drug (5-FU) was detected, indicating its absorption and bioavailability with excellent half-life of the PMBA for both routes of administration (IV and Oral), thereby indicating a new adjuvant therapy for KRAS mutant colon cancer.

【 授权许可】

Unknown