Natural compounds obtained from plants are capable of garnering considerable attention from the scientific community, primarily due to their ability to check and prevent the onset and progress of cancer. These natural compounds are primarily used due to their nontoxic nature and the fewer side effects they cause compared to chemotherapeutic drugs. Furthermore, such natural products perform even better when given as an adjuvant along with traditional chemotherapeutic drugs, thereby enhancing the potential of chemotherapeutics and simultaneously reducing their undesired side effects. Curcumin, a naturally occurring polyphenol compound found in the plant Curcuma longa, is used as an Indian spice. It regulates not only the various pathways of the immune system, cell cycle checkpoints, apoptosis, and antioxidant response but also numerous intracellular targets, including pathways and protein molecules controlling tumor progression. Many recent studies conducted by major research groups around the globe suggest the use of curcumin as a chemopreventive adjuvant molecule to maximize and minimize the desired effects and side effects of chemotherapeutic drugs. However, low bioavailability of a curcumin molecule is the primary challenge encountered in adjuvant therapy. This review explores different therapeutic interactions of curcumin along with its targeted pathways and molecules that are involved in the regulation of onset and progression of different types of cancers, cancer treatment, and the strategies to overcome bioavailability issues and new targets of curcumin in the ever-growing field of cancer.

Curcumin has long been known to posses medicinal properties and recent scientific studies have shown its efficacy in treating cancer. Curcumin is now considered to be a promising anti-cancer agent and studies continue on its molecular mechanism of action. Curcumin has been shown to act in a multi-faceted manner by targeting the classical hallmarks of cancer like sustained proliferation, evasion of apoptosis, sustained angiogenesis, insensitivity to growth inhibitors, tissue invasion and metastasis etc. However, one of the emerging hallmarks of cancer is the avoidance of immune system by tumors. Growing tumors adopt several strategies to escape immune surveillance and successfully develop in the body. In this review we highlight the recent studies that show that curcumin also targets this process and helps restore the immune activity against cancer. Curcumin mediates several processes like restoration of CD4+/CD8+ T cell populations, reversal of type-2 cytokine bias, reduction of Treg cell population and suppression of T cell apoptosis; all these help to resurrect tumor immune surveillance that leads to tumor regression. Thus interaction of curcumin with the immune system is also an important feature of its multi-faceted modes of action against cancer. Finally, we also point out the drawbacks of and difficulties in curcumin administration and indicate the use of nano-formulations of curcumin for better therapeutic efficacy.

SummaryTumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4 + CD25 + FoxP3 + T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-b (TGF-b) production in tumour cells that essentially blocked TGF-b-SMAD3/SMAD4-mediated induction of CD25/ interleukin-2 receptor a on CD4 + T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-b-induced Treg cell augmentation.

T-regulatory cells are an upsurge in the tumor microenvironment and induce immune-evasion. CD4+ Treg cells are well characterized whereas the role of CD8+ Tregs in cancer has recently started to crease attention. Here, we report an augmentation CD8+FOXP3+ Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4+ Treg cells. But how FOXP3 is induced and maintained in tumor-CD8+ Tregs is the Cinderella of the investigation. We observed that RUNX3, a CD8+ lineage-specific transcription factor, binds at the FOXP3-promoter to induce its transcription. In addition to promoter activation, involvement of cis-elements CNS1 and CNS2 in the transcriptional regulation of FOXP3 was also evident in these cells. SMAD3 binds to CNS1 region and acts as transcription inducer, whereas GATA3 plays a temporal role in the FOXP3 transcription by differential chromatin modification in CNS regions. In CNS1 region, GATA3 acts as a repressor for FOXP3 in naïve CD8+ T cells. Whereas in CD8+ Tregs, GATA3 binds directly at CNS2 region and persuaded the maintenance of FOXP3. Therefore, the intervention of these concerted transcriptional machinery may have a therapeutic potential in immunotherapy of cancer.

p53 preserves genomic integrity by restricting anomaly at the gene level. Till date, limited information is available for cytosol to nuclear shuttling of p53; except microtubule-based trafficking route, which utilizes minus-end directed motor dynein. The present study suggests that monomeric actin (G-actin) guides p53 traffic towards the nucleus. Histidine-tag pull-down assay using purified p53(1–393)-His and G-actin confirms direct physical association between p53 and monomeric G-actin. Co-immunoprecipitation data supports the same. Confocal imaging explores intense perinuclear colocalization between p53 and G-actin. To address atomistic details of the complex, constraint-based docked model of p53:G-actin complex was generated based on crystal structures. MD simulation reveals that p53 DNA-binding domain arrests very well the G-actin protein. Docking benchmark studies have been carried out for a known crystal structure, 1YCS (complex between p53DBD and BP2), which validates the docking protocol we adopted. Co-immunoprecipitation study using “hot-spot” p53 mutants suggested reduced G-actin association with cancer-associated p53 conformational mutants (R175H and R249S). Considering these findings, we hypothesized that point mutation in p53 structure, which diminishes p53:G-actin complexation results in mutant p53 altered subcellular localization. Our model suggests p53Arg249 form polar-contact with Arg357 of G-actin, which upon mutation, destabilizes p53:G-actin interaction and results in cytoplasmic retention of p53R249S.

Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.

Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.

NK cells recognize MHC class I (MHC-I) Ags via stochastically expressed MHC-I–specific inhibitory receptors that prevent NK cell activation via cytoplasmic ITIM. We have identified a pan anti–MHC-I mAb that blocks NK cell inhibitory receptor binding at a site distinct from the TCR binding site. Treatment of unmanipulated mice with this mAb disrupted immune homeostasis, markedly activated NK and memory phenotype T cells, enhanced immune responses against transplanted tumors, and augmented responses to acute and chronic viral infection. mAbs of this type represent novel checkpoint inhibitors in tumor immunity, potent tools for the eradication of chronic infection, and may function as adjuvants for the augmentation of the immune response to weak vaccines.