## 4 Colorectal Cancer  
Colorectal cancer (CRC) is considered a real public health problem worldwide due to its incidence and the lack of effective treatments in advanced stages [2; 34]. CRC is the third most common cancer and the second most common cause of death from cancer, representing between one and two million new cases each year. This mortality has a clear growth trend that has been shown to be related to lifestyle and diet [35]. Despite great advances in recent years, the treatment of CRC has not achieved satisfactory results in terms of a cure or reduction in incidence, especially in advanced stages of the disease in which there is metastatic expansion of the tumor (especially hepatic), drastically influencing patient survival. Surgery (if the tumor is resectable) and chemotherapy are the main treatments for CRC. The chemotherapy currently used is based on different chemotherapies, either as monotherapy or in combination (oxalipidatin, irinotecan, 5 FU,capeticabine, TAS-102, ralitrexed) [36]. In recent years, active biological drugs have been developed for advanced CRC, including the monoclonal antibodies cetuximab, panitumumab, and bevacizumab and a recombinant fusion protein (aflibercept) with very precise indications [37; 38; 39]. Despite this, the results are very limited, as clearly indicated by the median survival of these patients (15 to 20.5 months) [40]. The improvement in its prognosis, therefore, requires the development of new strategies that add therapeutic activity to preventive action [41; 42]. The development of new therapeutic strategies covers a large number of research fields that range from nanotechnology to the use of systems that activate the immune system or the use of extracts from different origins, among others, that can help improve the response to treatment. In this context, currently, the activity of plant extracts or derivatives in the viability and survival of tumor cells is attracting great interest [43]. One of the main reasons why chemotherapy loses efficacy is the emergence of MDR (Figure 2). This is why compounds of plant origin that act at the level of this resistance mechanism are currently being studied in order to develop effective therapies. Recently, many new potent plant-derived agents for reversing MDR have been discovered, most notably phenolic compounds and terpenoids. For example, triterpenoids isolated by the methanolic extraction of Momordica balsamina have been reported to have an effect on MDR proteins in colon cancer. Of all the compounds that were isolated, four of them (ballaminoside A, karavilagenin C, karavoates A, and karavoates E) acted on the modulation of P-gp in the HT-29 CRC cell line [44]. Different diterpenoids and coumarins isolated from various Euphorbia species have also been shown to modulate MDR, more specifically by inhibiting P-gp activity. Of all the isolates, Latilagascene B (isolated from the methanol extract of Euphorbia lagascae aerial parts) proved to be a very effective P-gp inhibitor in LoVo/Dx cells; however, it was not able to restore DOX cytotoxicity in these cells [45]. Other species of Euphorbia are also sources of bioactive compounds that act at this level. From methanolic extracts of the Hungarian Euphorbia species, several diterpenes with skeletons of jatrophan or latirano have been isolated. Of all the compounds isolated,  
Figure 2: Summary of modulation of MDR mechanism by natural bioactive compounds. (1) Inhibition of Nrf/MRP2, inducing MRP-2 downregulation. (2) P-gp and MRP-1 blocking by natural bioactive compounds. (3) Natural bioactive compounds inhibit glutamine cell intake and consequently induce MRP-1 dysfunction. compound 8 (isolated from the lipophilic phase of methanol extracts of Euphorbia serrulata) was the most potent, interacting synergistically when combined with epirubicin and acting as an effective lead compound for MDR reversal [46]. Besides terpenoid compounds, flavonoid and phenolic compounds also exhibit modulation of MDR [47].