**1. Introduction**

Citrus belongs to one of the most popular and important fruit crops that is widely grown in the world and supplies valuable and essential nutrients to the human diet. Citrus fruits depict a rich origin of naturally occurring biologically active compounds which are polyphenolic phytochemicals. Their abundant level of flavonoids, terpenes, phytonutrients and other phenolic compounds, carotenoids and vitamins C have been described [1]. Polyphenols are one of the major functional bioactive compounds available in citrus such as grapefruits (*Citrus paradisi)*, oranges (*Citrus sinensis*), lime (*Citrus aurantifolia*), tangerine (*Citrus reticulata*) and others. Consumption of polyphenols of more than 820 mg daily has been identified in several dietary sources including fruits and vegetables. Gradually, the consideration of polyphenolic compounds because of their therapeutic benefit is coming to play, as the world returns to nature to discover sources of prospective drug candidates [2, 3].

**Figure 1.** *Commonly found polyphenols in citrus fruits.*

Polyphenol represents a chemical compound with a structure that consists of one or more phenolic rings [4]. Further, classifications are done based on the number of phenolic rings and other structures associated with these rings (for example, oxygenated heterocycle) [5]. Polyphenols are most recognized for possession of unique structural features which include the flavan ring and many units of phenol. They are beneficial organic compounds placed into different subclasses (**Figure 1**). Currently, nearly 15,000 varieties have been recognized, wherein flavonoids represent one of the polyphenols [2]. Flavonoids' structure contains 15 carbon atoms that consist of two benzene rings, connected to a flavone ring. Oxidation of the heterocyclic ring can give rise to other subclasses such as flavanones, flavonols, flavones and anthocyanins. Citrus fruits such as lemons (*Citrus limon*), grapefruit, oranges and limes are sometimes referred to as citroflavonoids due to their richness in flavanones [6].

Multidrug resistance (MDR) of cancer and bacteria cells constitutes one of the main challenges and an obstacle that is usually encountered during chemotherapy, and this often results in chemotherapy failure [7]. Thus, the search for non-toxic modulators of MDR is of great importance and beneficial effect on enhancing the apoptosis of resistant cells. Even the rapid increase of microorganisms' resistance to antimicrobial drugs is currently a task to tackle, globally [8]. The emergence of bioactive compounds found in nature among plants or their products has been attracting the curiosity of researchers with a focus on the biological significance of citrus fruits as a possible and prospective source of pharmaceuticals [3].

Recently, studies have demonstrated the involvement of the mobilization of Phosphoinositide 3-kinase/protein kinase (PI3K/AKT), extracellular-signal-regulated kinase (ERK) and nuclear factor erythroid 2–related factor 2 (Nrf2) pathways in resisting the effects of chemotherapeutic drugs [9, 10].

Since anti-tumor drugs can inhibit these signaling pathways for increased sensitivity of tumor cells to chemotherapy drugs [11], identification of potent and potential inhibiting agents that can inhibit these pathways for reversal of MDR is necessary. Here, we discuss the consideration of natural products such as polyphenolic phytochemicals found in citrus fruits as prospective MDR modifiers since they are safe and harmless [12, 13].

*Inhibition of Multidrug Resistance by Polyphenolic Phytochemicals of Citrus Fruits DOI: http://dx.doi.org/10.5772/intechopen.107903*
