Dr Weeks Comment: Nitric Oxide (NO) is a small molecule which can play a powerful role in supporting people with cancer while they heal.

“…It is becoming increasingly clear that NO is involved in cancer immunity and can enhance the effectiveness of immunotherapies, chemotherapies, and radiotherapies. However, the effects of NO in cancer are highly dependent on the cancer cell type, the source of the NO, the localized concentration of NO, and changes in the tumor microenvironment. NO and NO donors have been clinically shown to have antitumor effects in certain cancers (Table 3). However, NO has also been shown to have various tumor-enhancing effects in triple-negative breast cancer [171], pancreatic cancer [172], melanoma [173], and oral cancer [174]…”

Antioxidants (Basel). 2019 Sep; 8(9): 407.Published online 2019 Sep 17. doi: 10.3390/antiox8090407

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Emily Hays and Benjamin Bonavida

READ the entire article at this SOURCE https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769868/#

Abstract

In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.

1.1. Cancer and Conventional Therapies

Cancer cells proliferate and survive by escaping the host’s regulatory systems through various mutations. These mutations lead to uncontrolled cell growth, tumorigenesis, metastasis, and death of the host. Different cancers have different types of mutations and cause disease through manipulating different cellular pathways and their environment. Thus, cancer therapies have been developed for different cancers that attempt to kill the cells through various mechanisms. One of the most common therapies is chemotherapy, which kills cells by damaging DNA and inhibiting mitosis [1]. Chemotherapy has led to significant clinical responses in many cancers, including increased cytotoxicity and prolonged overall and progression-free survivals, such as colorectal cancer [2], non-small-cell lung cancer [3], pancreatic cancer [4], and many others. Various combination chemotherapies have also shown to be more effective compared to single agent therapies in treating several cancers, such as advanced non-small-cell lung cancer [5] and metastatic breast cancer [6]. Another common method of treatment is radiotherapy, which uses high energy rays to kill cancer cells in a localized area [7]. Radiotherapy is often combined with other treatments and has been shown to be effective in treating cancers, such as rectal cancer, in combination with surgery [8] and chemotherapy [9]. Radiotherapy has also been shown to be effective in combination with immunotherapy in preclinical and some clinical studies because of its potential to change the tumor microenvironment and stimulate immune responses [10,11,12].

Immunotherapy aims to enhance the host’s innate, antibody, and cell-mediated immune attacks on cancer cells [13,14]. Remarkable progress has been made in recent years in cancer immunology and immunotherapies. Several recent therapeutic strategies, such as novel stimulator of interferon genes (STING) agonists, have been developed to enhance the host’s innate immune attack on cancer cells [15]. Helper-like innate lymphoid cells have also emerged as a new target for immunotherapies because of their ability to infiltrate the tumor microenvironment [16,17]. Targeted therapies, such as monoclonal antibodies, T-cell mediated therapies, and small molecule inhibitors aim to inhibit cancer cell growth, increase cell death, and restrict the spread of cancer. These targeted therapies target specific cancer proteins or molecular pathways and are preferred because they minimize the death of normal cells and specifically target cancer cells. Among the most notable targeted immunotherapies are checkpoint inhibitor therapies. Thus, antibodies that block the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), the programmed cell death receptor 1 (PD-1), or the programmed cell death ligand 1 (PD-L1) have been successful in enhancing the host’s attack on various tumor types, including melanoma, lung, bladder, and many others [14]. Cell-based immunotherapy is another targeted therapy approach. Because low numbers of tumor infiltrating lymphocytes (TILs) are correlated with poor survival in some cancers, cell-based immunotherapy aims to increase this number by isolating TILs from a patient’s specimen, expanding them in vitro, and re-infusing them back into the patient. However, this approach requires tumors with many antitumor T cells, which is uncommon in most tumors, and the process is difficult, labor intensive, and time consuming [18]. Thus, more advanced approaches have been developed in recent years, including adoptive cell transfer (ACT). In this approach, a patient’s T-cells are genetically modified with receptors for specific cancer antigens. T-cells can be modified with either T-cell Receptors (TCRs) or Chimeric Antigen Receptors (CARs). Since TCRs can only recognize antigens when presented on Major Histocompatibility Complexes (MHCs), the TCR approach is limited because many cancers downregulate the expression of MHCs on the surface of the cell. Additionally, TCRs can recognize small peptide epitopes and may cross-react with self-antigens [18]. However, CAR T-cell therapy uses chimeric proteins, which link antibodies that target tumor cell surface antigens to intracellular signaling receptors for TCRs. Both Phase I and Phase II clinical trials of an anti-CD19 CAR T-cell therapy, axicabtagene ciloleucel (axi-cel), showed efficacy in patients with B-cell lymphomas. In the phase II trial, the objective response rate was 82%, and the complete response rate was 54% [19]. Axi-cel was FDA-approved in 2017 for use in patients with large B-cell lymphoma and produced durable responses in most patients; however, some patients experienced cytokine release syndrome and other undesired side effects [20].

Small molecule inhibitors are another type of targeted cancer therapy. Various small molecules have been used to constrain cancer cell growth and survival. Their mechanisms of action can vary from inhibiting growth pathways to targeting apoptotic regulators, inhibiting proteins to reactivate p53 function, or targeting proteins, such as Hsp90, that promote malignant transformation. Small molecule inhibitors, such as these, have shown significant antitumor effects, including the increased apoptosis of tumor cells, and improved clinical outcomes in various types of cancer [21,22,23]. Small molecule inhibitors can also sensitize tumor cells to other therapies. Selective small molecules, such as DNA inhibitors, were found to sensitize cancer cells to chemotherapy [24]. Combinations of small molecule inhibitors can also sensitize radiation therapy-resistant cancer cell lines [25].