**3. Anticancer activities of curcumin**

There were 19.3 million new cancer cases and 10.0 million cancer-related deaths reported in 2020, worldwide [74]. Considering the increasing cancer statistics and the cost of cancer treatments, finding effective and economically viable methods for patients in low- and middle-income countries is crucial. Cancer-related studies showed that curcumin-induced apoptosis and inhibited proliferation in cancer cells through the activation of the mitochondria-mediated pathway [75], ROS generation [76], and the activation of caspase-3 [77]. Other study suggested that curcumin compounds can prevent either the formation or spread of tumor by inducing apoptosis and inhibiting cell proliferation through antiangiogenic effects [78]. Inhibition of tumor invasion by curcumin is mediated by reducing the modification of the matrix metalloproteases (MMPs), the cell surface proteins NF-κβ, TNF-α, cyclooxygenase-2 (COX-2), chemokines, and growth factors (HER-2, EGFR) [79, 80]. In some tumors, curcumin inhibited angiogenesis by suppressing angiogenic cytokines such as IL-6, IL-23, and IL-1β [81].

Cancer and inflammation have a strong relationship, so the anti-inflammatory effects of curcumin would likely result in antitumor effects. According to Pulido-Moran et al. [81], curcumin prevented the development of several types of cancer by reducing the production of mediators of inflammation, such as COX-2 and lipoxygenase 2. The antitumor effect of curcumin has been shown in breast cancer [82], lung

cancer [83], leukemia [84], gastric cancer [85], colorectal cancer [86], esophageal cancer [87] and prostate cancer [88]. Curcumin has been shown to regulate key processes involved in cancer development and progression (**Figure 2**).

### **3.1 Induction of apoptosis**

As a form of cell death, apoptosis is a highly regulated physiological process, which removes not only damaged, mutated, aged, and unrepairable cells, but also preserves the integrity and health of the entire organism. Apoptosis imbalances, either excessive or insufficient, may contribute to a variety of diseases including cancer [89, 90]. As a cancer cell growth inhibitor, curcumin modulates multiple cellular signaling pathways such as those that induce apoptosis in several cancers including breast [91], malignant pleural mesothelioma [92], gastric cancer [93], acute lymphoblastic leukemia [94], lung cancer [95], pancreatic cancer [96] and gallbladder carcinoma [97].

Curcumin potentiate apoptosis in cancer due to its ability to induce increased activation of Bax [92], cleavage of poly (ADP-ribose) polymerase (PARP) [92], blocking the PI3K-Akt–mTOR signaling pathway [98, 99], dephosphorylation of Bad [95] and the downregulation of Bcl-2 proteins [96].

**Figure 2.** *Cancer processes regulated by curcumin.*

*Germicidal and Antineoplastic Activities of Curcumin and Curcumin-Derived Nanoparticles DOI: http://dx.doi.org/10.5772/intechopen.103076*

#### **3.2 Modulation of cell survival pathways**

A number of signaling pathways have been shown to drive unregulated selfrenewal and differentiation in cells leading to cancer [100–102]. The antitumor activities of curcumin have been studied extensively; a growing body of evidence indicates that curcumin is involved in the inhibition of growth/proliferation pathways and activation of cell death pathways [103–107]. The fact that curcumin acts through multiple signaling pathways makes it unlikely to develop resistance.

Curcumin regulates multiple cell survival signaling pathways including Wnt/βcatenin pathway [104], NF-κB signaling pathway [105], PI3K/Akt signaling pathway [106], and JAK-STAT3 pathway [107], which regulate different sets of target genes that are involved in cell proliferation, cell survival, and differentiation. The regulation of these cell survival pathways by curcumin has been demonstrated in breast cancer [99, 105], colon cancer [104], bladder cancer [106], lung cancer [108], and liver cancer [109].

#### **3.3 Inhibition of metastasis**

Relapse of cancer patients is commonly attributed to cancer invasion and migration, and researchers have been focusing their attention on invasion as an important step in metastasis [110]. Curcumin has shown promising potential for the treatment of cancer by inhibiting metastasis, previous studies have shown that curcumin reduces cancer metastasis by suppressing NF-kB and matrix metalloproteinases (MMPs) expression in cancer animal models [111, 112]. Tumor metastasis is promoted by NF-kB through modulation of cell adhesion molecules including selectins, integrins, and their ligands, NF-kB also induces epithelial-mesenchymal transition, which aids distant metastasis [113]. MMPs also show similar mechanisms by degrading extracellular matrix components resulting in tumor cell migration [114].

Research on the anti-metastasis effect of curcumin continues to pile up, and Sreenivasan et al. [115] showed that curcumin inhibited the metastasis of nasopharyngeal carcinomas (NPCs) by inhibiting miR-125a-5p as a consequence, increasing p53 expression. In prostate cancer, the anti-metastasis effect of curcumin was achieved by decreasing miR-21 and increasing phosphatase and tensin homolog (PTEN) [116]. A recent study of the anti-metastasis effect of curcumin is shown in gastrointestinal cancers, according to this study, curcumin inhibited cell invasion in these cells [117], these results suggest that curcumin inhibits metastasis in cancer by targeting multiple anticancer pathways.

Despite the advantages of curcumin in treating different diseases, the insolubility of curcumin contributes to its poor oral bioavailability and low chemical stability, which limits its application [13, 38, 39]. Moreover, the cellular uptake of curcumin is low, as a result of its hydrophobicity, curcumin penetrates into the cell membrane and binds to the fatty acyl chains of membrane lipids through hydrogen bonds and hydrophobic interactions, resulting in low curcumin levels inside the cytoplasm [56, 118]. These curcumin challenges are resolved by the use of nanoformulations.
