The effect of novel nitrogen-based chalcone analogs on colorectal cancer cells: Insight into the molecular pathways

Arij Fouzat Hassan; Ola Hussein; Tara Al-Barazenji; Asma Allouch; Layla Kamareddine; Ahmed Malki; Ala-Eddin Al Moustafa; Ashraf Khalil

doi:10.1016/j.heliyon.2024.e27002

The effect of novel nitrogen-based chalcone analogs on colorectal cancer cells: Insight into the molecular pathways

Heliyon. 2024 Feb 27;10(5):e27002. doi: 10.1016/j.heliyon.2024.e27002. eCollection 2024 Mar 15.

Authors

Arij Fouzat Hassan¹, Ola Hussein¹, Tara Al-Barazenji², Asma Allouch², Layla Kamareddine^{2

3}, Ahmed Malki², Ala-Eddin Al Moustafa^{3

4

5}, Ashraf Khalil¹

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
² Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar.
³ Biomedical Research Centre, Qatar University, Doha, Qatar.
⁴ College of Medicine, QU Health, Qatar University, Doha, Qatar.
⁵ Oncology Department, McGill University, Montreal, QC, Canada.

Abstract

In colorectal cancer (CRC), aberrations in KRAS are associated with aggressive tumorigenesis and an overall low survival rate because of chemoresistance and adverse effects. Ergo, complementary, and integrative medicines are being considered for CRC treatment. Among which is the use of natural chalcones that are known to exhibit anti-tumor activities in KRAS mutant CRC subtypes treatment regimens. Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation. These compounds were synthesized in our lab and previously reported to exhibit potent activity against breast cancer cells. Our data revealed that DK13 and DK14 treatment suppress cell growth, disturb the progression of cell cycle, and trigger apoptosis in CRC cell lines. Besides, treatment with both compounds impedes cell invasion and colony formation in both cell lines as compared to 5-FU; this is accompanied by up and down regulations of E-cadherin and Vimentin, respectively. At the molecular level, both compounds deregulate the expression and phosphorylation of β-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through β-catenin/Akt/mTOR signaling pathways.

Keywords: Analogs; Chalcone; Colorectal cancer (CRC); Epithelial-mesenchymal transition (EMT); Methoxy; Nitrogen mustard.