Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells

Zohra Nausheen Nizami ¹ Mazoun Al Azzani ¹ Samah Khaldi ¹ Adil Farooq Wali ² Rym Magramane ¹ Shamaa Abdul Samad ¹ Ali H. Eid ³ Kholoud Fayyad Arafat ¹ Yusra Saif Al Dhaheri ¹ Samir Attoub ¹ Rabah Iratni ^1*

• ¹ United Arab Emirates University, Al-Ain, United Arab Emirates
• ² RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
• ³ Qatar University, Doha, Qatar

Colorectal cancer is a leading cause of cancer related-death worldwide, and resistance to 5-fluorouracil, a key component of chemotherapy regimens, is a major clinical concern. Here, we explored the anticancer effects of Rhus coriaria ethanolic extract in parental (HCT-116-WT) and 5FU-resistant HCT-116 (HCT-116-5FU-R) CRC cells. We previously elucidated its anticancer effects in triple-negative breast cancer, CRC, and pancreatic cancer cells. Herein, we found that RCE inhibited the viability and colony formation and growth capacities of HCT-116-WT and HCT-116-5FU-R cells. The antiproliferative effects were attributed to DNA damage-mediated impairment of cell cycle at S phase, and induction of Beclin-1-independent autophagy in both cell lines. Mechanistically, inhibition of the mTOR, STAT3 and p38 MAPK pathways was implicated in the latter. Additionally, RCE induced caspase-7-independent apoptosis in HCT-116-WT cells. However, HCT-116-5FU-R cells were resistant to apoptosis through upregulation of survivin, and downregulation of Bax. Using autophagy and proteasome inhibitors, we clarified that autophagy and the proteasome pathway contributed to RCE-mediated cell death in HCT-116-WT and HCT-116-5FU-R cells. Lastly, we confirmed RCE inhibited the growth of both HCT-116-WT and HCT-116-5FU-R xenografts in a chick embryo model. Collectively, our findings highlight that RCE is a source of phytochemicals that can be used as anticancer agents for 5FU-resistant CRC.