Nobiletin in Cancer Therapy; Mechanisms and Therapy Perspectives.

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.

Resveratrol in Cancer Therapy: From Stimulation of Genomic Stability to Adjuvant Cancer Therapy: A Comprehensive Review.

Cancer therapy through anticancer drugs and radiotherapy is associated with several side effects as well as tumor resistance to therapy. The genotoxic effects of chemotherapy and radiotherapy may lead to genomic instability and increased risk of second cancers. Furthermore, some responses in the tumor may induce the exhaustion of antitumor immunity and increase the resistance of cancer cells to therapy. Administration of low-toxicity adjuvants to protect normal tissues and improve therapy efficacy is an intriguing strategy. Several studies have focused on natural-derived agents for improving the antitumor efficiency of radiotherapy, chemotherapy, and novel anticancer drugs such as immunotherapy and targeted cancer therapy. Resveratrol is a naturally occurring substance with intriguing antioxidant, cardioprotective, anti-diabetes, and antitumor properties. Resveratrol has been demonstrated to modulate tumor resistance and mitigate normal tissue toxicity following exposure to various drugs and ionizing radiation. Compelling data suggest that resveratrol may be an appealing adjuvant in combination with various anticancer modalities. Although the natural form of resveratrol has some limitations, such as low absorption in the intestine and low bioavailability, several experiments have demonstrated that using certain carriers, such as nanoparticles, can increase the therapeutic efficacy of resveratrol in preclinical studies. This review highlights various effects of resveratrol that may be useful for cancer therapy. Consequently, we describe how resveratrol can protect normal tissue from genomic instability. In addition, the various mechanisms by which resveratrol exerts its antitumor effects are addressed. Moreover, the outcomes of combination therapy with resveratrol and other anticancer agents are reviewed.

Modulation of the immune system by melatonin; implications for cancer therapy.

Immune system interactions within the tumour have a key role in the resistance or sensitization of cancer cells to anti-cancer agents. On the other hand, activation of the immune system in normal tissues following chemotherapy or radiotherapy is associated with acute and late effects such as inflammation and fibrosis. Some immune responses can reduce the efficiency of anti-cancer therapy and also promote normal tissue toxicity. Modulation of immune responses can boost the efficiency of anti-tumour therapy and alleviate normal tissue toxicity. Melatonin is a natural body agent that has shown promising results for modulating tumour response to therapy and also alleviating normal tissue toxicity. This review tries to focus on the immunomodulatory actions of melatonin in both tumour and normal tissues. We will explain how anti-cancer drugs may cause toxicity for normal tissues and how tumours can adapt themselves to ionizing radiation and anti-cancer drugs. Then, cellular and molecular mechanisms of immunoregulatory effects of melatonin alone or combined with other anti-cancer agents will be discussed.