No abstract

Immune reactions are involved in both tumour and normal tissue in response to therapy. Elevated secretion of certain chemokines, exosomes and cytokines triggers inflammation, pain, fibrosis and ulceration among other normal tissue side effects. On the other hand, secretion of tumour-promoting molecules suppresses activity of anticancer immune cells and facilitates the proliferation of malignant cells. Novel anticancer drugs such as immune checkpoint inhibitors (ICIs) boost anticancer immunity via inducing the proliferation of anticancer cells such as natural killer (NK) cells and CD8+ T lymphocytes. Certain chemotherapy drugs and radiotherapy may induce anticancer immunity in the tumour, however, both have severe side effects for normal tissues through stimulation of several immune responses. Thus, administration of natural products with low side effects may be a promising approach to modulate the immune system in both tumour and normal organs. Resveratrol is a well-known phenol with diverse effects on normal tissues and tumours. To date, a large number of experiments have confirmed the potential of resveratrol as an anticancer adjuvant. This review focuses on ensuing stimulation or suppression of immune responses in both tumour and normal tissue after radiotherapy or anticancer drugs. Later on, the immunoregulatory effects of resveratrol in both tumour and normal tissue following exposure to anticancer agents will be discussed.

The incidence of cancer has been growing worldwide. Better survival rates following the administration of novel drugs and new combination therapies may concomitantly cause concern regarding the long‐term adverse effects of cancer therapy, for example, second primary malignancies. Moreover, overcoming tumour resistance to anticancer agents has been long considered as a critical challenge in cancer research. Some low toxic adjuvants such as herb‐derived molecules may be of interest for chemoprevention and overcoming the resistance of malignancies to cancer therapy. Apigenin is a plant‐derived molecule with attractive properties for chemoprevention, for instance, promising anti‐tumour effects, which may make it a desirable adjuvant to reduce genomic instability and the risks of second malignancies among normal tissues. Moreover, it may improve the efficiency of anticancer modalities. This paper aims to review various effects of apigenin in both normal tissues and malignancies. In addition, we explain how apigenin may have the ability to protect usual cells against the genotoxic repercussions following radiotherapy and chemotherapy. Furthermore, the inhibitory effects of apigenin on tumours will be discussed.

Cancer has remained to be one of the major challenges in medicine and regarded as the second leading cause of death worldwide. Different types of cancer may resist anti-cancer drugs following certain mutations such as those in tumor suppressor genes, exhaustion of the immune system, and overexpression of drug resistance mediators, which increase the required concentration of anticancer drugs so as to overcome drug resistance. Moreover, treatment with a high dose of such drugs is highly associated with severe normal tissue toxicity. Administration of low-toxic agents has long been an intriguing idea to enhance tumor suppression. Naturally occurring agents e.g., herb-derived molecules have shown a dual effect on normal and malignant cells. On the one hand, these agents may induce cell death in malignant cells, while on the other hand reduce normal cell toxicity. Nobiletin, one of the well-known polymethoxyflavones (PMFs), has reportedly shown various beneficial effects on the suppression of cancer and the protection of normal cells against different toxic agents. Our review aims to explain the main mechanisms underlying nobiletin as an inhibitor of cancer. We have reviewed the mechanisms of cancer cell death caused by nobiletin, such as stimulation of reactive oxygen species (ROS), modulation of immune evasion mechanisms, targeting tumor suppressor genes, and modulation of epigenetic modulators, among others; the inhibitory mechanisms of nobiletin affecting tumor resistance properties such as modulation of hypoxia, multidrug resistance, angiogenesis, epithelial-mesenchymal transition (EMT) have been fully investigated. Also, the inhibition of anti-apoptotic and invasive mechanisms induced by nobiletin will later be discussed. In the end, protective mechanisms of nobiletin on normal cells/tissue, clinical trial results, and future perspectives are reviewed.

Induction of cell death and inhibition of cell proliferation in cancer have been set as some of the main goals in anti-tumor therapy. Cancer cell resistance leads to less efficient cancer therapy, and consequently, to higher doses of anticancer drugs, which may eventually increase the risk of serious side effects in normal tissues. Apigenin, a nature-derived and herbal agent, which has shown anticancer properties in several types of cancer, can induce cell death directly and/or amplify the induction of cell death through other anti-tumor modalities. Although the main mechanism of apigenin in order to induce cell death is apoptosis, other cell death pathways, such as autophagic cell death, senescence, anoikis, necroptosis, and ferroptosis, have been reported to be induced by apigenin. It seems that apigenin enhances apoptosis by inducing anticancer immunity and tumor suppressor genes, like p53 and PTEN, and also by inhibiting STAT3 and NF-κB signaling pathways. Furthermore, it may induce autophagic cell death and ferroptosis by inducing endogenous ROS generation. Stimulation of ROS production and tumor suppressor genes, as well as downregulation of drug-resistance mediators, may induce other mechanisms of cell death, such as senescence, anoikis, and necroptosis. It seems that the induction of each type of cell death is highly dependent on the type of cancer. These modulatory actions of apigenin have been shown to enhance anticancer effects by other agents, such as ionizing radiation and chemotherapy drugs. This review explains how cancer cell death may be induced by apigenin at the cellular and molecular levels.