The possible drug for cancer and metastasis prevention

Abstract

Future Drug DiscoveryVol. 4, No. 2 EditorialOpen AccessThe possible drug for cancer and metastasis preventionVladimir N PakVladimir N Pak *Author for correspondence: E-mail Address: oncoshut@gmail.comhttps://orcid.org/0000-0002-2009-0416Freelance Researcher, Toronto, ON, CanadaSearch for more papers by this authorPublished Online:18 May 2022https://doi.org/10.4155/fdd-2022-0008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: alpha-fetoproteincancerdendritic cellimmunotherapymyeloid-derived suppressor cellnatural killer cellneonatal Fc receptorOnly those who attempt the absurd can achieve the impossible.– Albert EinsteinOne in two people will be diagnosed with cancer in their lifetime in developed countries. Prophylactics and early diagnostics are recommended to everyone. On the other hand, even after the treatments, 90% of cancer patients die of metastasis. Early cancer and metastasis prevention drugs are in demand.Natural killer (NK) cells are key effector cells in cancer immune surveillance. They eliminate tumors, particularly at the initial stages, and play an essential role in tumors and metastases prevention. These cells rapidly kill any foreign cells without prior immunization or MHC I restrictions. NK cells are the primary effectors of innate immunity, as they can destroy low-differentiated cancer stem cells and metastasis.During pregnancy and cancer, myeloid-derived suppressor cells (MDSCs) suppress both innate (including NK cells) and adaptive immunity [1]. MDSCs are a small heterogeneous cell population of immature myeloid progenitors of granulocytes, macrophages and dendritic cells (DCs) at different stages of differentiation generated from a common hematopoietic stem cell in the bone marrow. Targeting MDSCs through multiple approaches increases the antitumor activity of NK cells and increases the efficacy of other therapies.Surprisingly the ‘magic target’ for cancer treatment/prevention is not the cancer cell itself. Depleting MDSCs unleashes the natural processes of NK and cytotoxic T-cells activation to erase cancer cells and metastases [2]. MDSCs were specifically depleted by the α-fetoprotein (AFP)-daunorubicin conjugate [3]. Next, AFP-maytansine conjugate lead to a statistically significant reduction in tumor volume in mice compared with control groups. There was 100% survival in the AFP-maytansine group of ten animals at day 60, compared with 0% survival in the control group by day 38 [4]. It comes out that AFP-toxin is powerful cancer immunotherapy and, to a less extent, a cancer cells-targeted magic bullet [5].AFP binds compounds naturallyToxins can be chemically conjugated to AFP or its fragments [6]. On the other hand, the serum carrier/transport function of mammalian AFPs was found to be more than 50 different biochemical known compounds [7]. During pregnancy, AFP transfers polyunsaturated fatty acid (PUFA) from the mother to the embryo. The transportation through the placenta goes without AFP-PUFA complex dissociation. Unlike in the placenta, in embryo cells, PUFA is released while AFP goes back for the next PUFA shuttle delivery.Small amounts of AFP naturally exist in the blood because an AFP/AFP receptor (AFPR) autocrine system operates in normal and malignant blood mononuclear cells [8]. Like during pregnancy, AFP can potentiate the activity of compounds with a known high binding affinity, such as diethylstilbestrol, warfarin, quercetin, etc. [7]. The known antitumor activity of moderate toxins: ajoene, capsaicin, sinigrin, gossypol, astaxanthin, etc. can be explained by AFP shuttle delivery to AFP-binding immune and cancer cells. For example, AFP can potentiate paclitaxel antitumor action. In low doses, paclitaxel is not able to directly suppress tumor cell proliferation, induce apoptosis or alter the bone marrow hematopoiesis, but it significantly decreased the accumulation and immunosuppressive activities of tumor-infiltrating MDSCs. It has also reversed immunosuppression and chronic inflammation. Low non cytotoxic doses of paclitaxel modulate the functions of MDSCs in primary skin tumors and lymphoid organs, affect the production of mediators of chronic inflammation and T-cell activities, prolong mice survival and reduce the melanoma burden. They have also been used for enhancing the efficacy of accompanying anticancer therapies [9].Exogenous AFP complexes with dioxin, acetoxychavicol, genistein, curcumin, paclitaxel and other selected toxins inhibited tumor growth in mice and some of them can be applied to cancer patients [10].AFP can shuttle AFP-binding drugs present in the patient’s blood. AFP and amphotericin B have shown response in six out of eight cancer patients. The cytokine storm-like reaction with fever and shivering observed immediately during the drugs infusions in patients indicates the immunotherapy action of the complex that depleted MDSCs in the blood ahead of cancer cells. The unleashed immune system eliminates the cancer cells [10].Nevertheless, injection is not an option for cancer and metastasis prevention in everyone during a lifetime. When you ask what patients want – obviously, they want appropriate therapy that works. But if you ask if they want an infusion or an oral drug, most would want an oral drug.However, oral administration is in general not feasible for protein drugs. Unenhanced bioavailability for oral administration for protein/peptide pharmaceuticals accounts for no more than 0–1% of the primary dose [11]. It seems absurd to take AFP-toxin orally.AFP–toxin oral administrationSome stomach cancers, as well as colon and gastric carcinomas, produce AFP. A high level of AFPR has been detected in gastric cancers. Therefore, AFP–toxin oral formulations can be used at least to treat AFPR-positive GI tract cancers [10].A small amount of AFP is produced by almost all cells of the human GI tract. There should be cells that reabsorb the AFP or AFP-nutrient complex back. These can be AFPR-positive stem or regenerating cells of the GI tract. On the other hand, very little albumin is lost in the GI tract. It is possible that any proximal transport of albumin into the intestinal lumen might be compensated for by the neonatal Fc receptor (FcRn)-reuptake or alternately by reabsorption. Such mechanisms might explain the progressive increase in FcRn expression levels from the duodenum to the proximal colon [12]. An adult human gut enterocytes transport the compounds absorbed from the intestine through FcRn-mediated endocytosis. The FcRn controls the fate of three very distinct delivery proteins: IgG, albumin and AFP, through a highly similar mode of binding [13]. FcRn-dependent transcytosis in the gut has been established for IgG and albumin [14].AFP competes with IgG for FcRn binding and has an apparent effect on decreasing IgG levels in preclinical studies. AFP is a high-value FcRn antagonist and can be applied in more than forty autoimmune diseases driven by autoantibodies. It has a similar clinical value to other ligands and monoclonal antibodies in a development (argenx, UCB, affibody) that blocks FcRn activity. The two common side effects reported for FcRn modulators – a headache or a decrease in albumin levels – were not detected during AFP treatments. Recombinant AFP (ACT-101) is currently undergoing the process of drug registration for inflammatory bowel disease, multiple sclerosis, myasthenia gravis, Hashimoto disease and others.IgG loaded with antigens is absorbed from the intestine and reaches FcRn-positive DCs in the lymph nodes. AFP that demonstrates a higher than albumin binding affinity to FcRn [13] can be assumed to transfer its load through enterocytes without dissociation, similar to the IgG antigen complex [15].Cancer treatment with oral porcine AFP & AFP-binding toxinsPorcine AFP (pAFP) is close to but not identical to AFP, with a high homology of the amino acid structure and similar immunologic properties. PAFP-rotenone complex has shown tumor-inhibiting properties in mice models [10]. Nevertheless, an investigation conducted addressing the possible transport properties of pAFP or pAFP-rotenone has shown their absence in both the free form and in the complex with the toxin in the blood after mice gavage. So, unlike injectable, oral pAFP-toxin complex could not reach the blood and deplete MDSCs or distant cancer cells through the AFPR.MDSCs are abundant in the peripheral blood of cancer patients and suppress NK cell antitumor activity, but they are barely detectable in the lymph nodes of healthy subjects. In peripheral lymphoid organs, MDSCs differentiates into DCs and macrophages [16]. In the lamina propria, human monocyte-derived DCs have FcRn, which transports the IgG-antigen to degrade compartments involved in the antigen presentation. DCs processes intestinal antigens, inducing the production of proper suppressor cells that, in turn, induce tolerance to food antigens. The intestinal DCs secrete proteins that suppress the activation of helper cells; thereby, preventing intestinal inflammations.By reducing the antigen-presenting capacity of monocytes/macrophages, AFP functions as an essential factor in the downregulation of the entire immune system in cancer [17]. AFP action on DCs is known to impair the activation of NK cells, similar to MDSCs [18]. On the opposite, like MDSC in the blood, the depletion of FcRn-positive DCs/macrophages [19] in the lamina propria and the gut lymph nodes leads to immune system activation and eventually to distant metastasis elimination. This mechanism of the pAFP-toxin complex action needs research. In any case, oral pAFP complexes with atractyloside, thapsigargin, rotenone, betulinic acid, ajoene and to the least extent with isotretinoin, tocotrienol and vitamin D3 work as cancer immunotherapy in mice [10].The suboptimal doses of the oral pAFP-atractyloside complex have shown a response in six out of 12 metastatic colorectal cancer patients [20]. Unlike injections, prolonged absorption of the complex in the gut does not induce cytokine storm-like reactions. A complete response was observed with small metastases. A better outcome can be expected from an early intake of the complex. In the additional trial, the doses of the pAFP-atractyloside complex were elevated, and the patient with stage IV ovarian cancer survived over 10 years [10].The pAFP-betulinic acid and pAFP-ajoene complexes demonstrated better tumor-inhibiting activity among those that can be permitted as supplements. Taken once or twice a year course, they can serve as a check-up of the immune system and prevent cancer and metastasis at the early stages.Future perspectiveAFP will pass the drug registration and be available for autoimmune, cancer and other diseases treatments. AFP chemical conjugate or AFP non-covalent complex with potent toxin will be used as injectable or oral drug for cancer and metastasis treatment. Porcine AFP with moderate toxins from traditional medicine can be manufactured as supplements for cancer prophylactics.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/