Synergistic combination of PMBA and 5-fluorouracil (5-FU) in targeting mutant KRAS in 2D and 3D colorectal cancer cells
2022
Qayum, Arem | Magotra, Asmita | Shah, Syed Mohmad | Nandi, Utpal | Sharma, P.R. | Shah, Bhahwal Ali | Singh, Shashank Kumar
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.
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