# Effect of _Allium sensecens_ Extract on Sorafenib Resistance in Hepatocarcinoma Cells
## 1 Introduction  
Hepatocellular carcinoma (HCC) is a common liver cancer with approximately 75% of the cases occurring in Asia and Africa [1]. Although various therapies, including liver transplantation, surgical resection, radioembolization, radiofrequency ablation, and transarterial chemoembolization [2] have been developed to manage HCC, drug resistance occurs frequently with continuous chemotherapy [3, 4] and combinatorial therapy [3, 4].  
Sorafenib, a multi-target kinase inhibitor, suppresses the proliferation and viability of cancer cells as well as inhibits angiogenesis in breast, skin, pancreatic, colon, and liver cancers [5, 6]. It activates the production of reactive oxygen species (ROS), eventually leading to the activation of ROS-mediated apoptotic pathways in HCC cells [7]. Sorafenib exhibits its action by targeting several signaling pathways/molecules: mitogen-activated protein kinase (MAPK) signaling pathway, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), and autophagy activation through iron regulatory protein (IRE), mammalian target of rapamycin (mTOR), and Beclin [6]. Although sorafenib is an effective HCC treatment option, the survival time of HCC patients can be shortened because of possible drug resistance [5]. In such a case, resistant cells prevent cellular apoptosis through the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, autophagy, and epithelial-mesenchymaltransition [8]. Moreover, resistant cells alter the tumor microenvironment by increasing the expression of hypoxia-inducible factor-1\(\alpha\) (HIF-1\(\alpha\)), also known as VEGF inducer, and multidrug resistance 1 (_MDR1_) gene activator [9].  
The protein of relevant evolutionary and lymphoid interest (PRELI) plays an important role in cellular protection under several stress conditions, including chemotherapy, desiccation, and osmotic imbalance [10]. Additionally, PRELI contains tandem repeats of the late embryogenesis abundant (LEA) protein [10]. We previously reported that [11] group 3 LEA (G3 LEA) induces drug resistance by modulating ATP-binding cassette (ABC) transporters and decreasing of ROS production in _Enterococcus facecium_.  
_Allium sensecens_, commonly known as German garlic from the lily family, is a perennial herb rich in flavonoids [12]. Reportedly, _A. sensecens_ extract attenuates carcinogenesis [13], modulates enzyme activities [14], and possesses antioxidant [15], antithrombotic [13], and antimutagenic [16] properties. Although many studies have been documented, to the best of our knowledge, there is none available on the effects of the _A. sensecens_ extract on drug resistance.  
The present study documents the bioactive substances involved in modulating PRELI expression and the attenuation of drug resistance in HCC cells. Our findings suggest that _A. sensecens_ extract and \(p\)-coumaric acid can potentially act as functional biomaterials to suppress drug resistance in HCC cells when treated with sorafenib. Although we propose a further in vivo experiment and research on PRELI signaling, the current findings suggest that PRELI is a key protein to attenuate drug resistance and that the extract is an optimal substance for application as a biofunctional material for pharmaceuticals and as a functional food.