Global Journal of Medical Research, F: Diseases, Volume 23 Issue 2

10 Year 2023 Global Journal of Medical Research Volume XXIII Issue II Version I ( D ) F © 2023 Global Journals A Cancer Prevention and Treatment Opportunity After toxin unloading, AFP can work as a shuttle and deliver additional toxins. DHA-daunomycin conjugate binds AFP and inhibits tumor growth in AFP-producing mice [33]. Most cancers do not produce AFP, but >80% are AFPR-positive; hence, exogenous AFP with toxins kills them. Thus, the treatment with AFP and amphotericin B in the excess (1:60-100) for shuttling demonstrated a response in 6 out of 8 cancer patients and increased quality of life [34]. The cytokine storm-like reaction, sometimes observed during the AFP with amphotericin B infusions, preceded cancer cells’ death, and it can indicate the consequences of MDSCs death [18]. The potent AFP-binding toxins are expected to provide even better than AFP-amphotericin B response in cancer treatments. Cancer cells can activate an AFP/AFPR autocrine loop (Fig. 2, B) [35, 36]. MDSCs are progenitor cells with only a few duplication steps from stem and embryo cells, and, as well as CSCs; they should retain an AFP-mediated nutrient delivery system. These need research. At least, AFP is absorbed by MDSCs, stimulating their suppressive activity [37, 38]. AFP attracts MDSCs and T regs through AFP- binding C-C chemokine receptor type 5 (CCR5) [39-41]. These regulatory cells migrate, accumulate, and suppress the immune attack on cancer. Targeting CCR5 reboots immunosuppressive myeloid cells [42, 43]. AFP binds to the neonatal Fc receptor (FcRn) [44, 45]. The FcRn is found in MDSCs in pancreatic cancer monocytes. MDSCs and DCs are elevated in pancreatic cancer patients compared to non-cancer donors [46]. They can be targeted through AFPR and/or FcRn by AFP-toxin drugs. AFPR, CCR5, and FcRn are valuable MDSCs markers, at least for a transitory period. Many current drugs do not eliminate CSCs, which may be why many cancers regrow after treatment. Immunotherapy does not act directly on cancer but works on the immune system. Checkpoint inhibitors and CAR T-cells are too unsafe for early-stage cancer; complexity and cost also prevent their application. Dissemination of cancer cells from the primary tumor into distant body tissues and organs is the leading cause of death in cancer patients. While most clinical strategies aim to reduce or impede the growth of the primary tumor, no treatment to eradicate metastatic cancer exists at present [47]. The MDSCs- and CSCs- targeting drugs have a bright future as they are critical in tumor and metastasis prevention [48, 49]. More than 100 years ago, Paul Ehrlich proposed a “magic bullet” that kills cancer cells, sparing the healthy ones. Nevertheless, this approach did not elevate the survival rate of cancer patients. The additional target outside of cancer cells should be hit. This “magic target” is a myeloid suppressor cell. Combining “magic bullets” and the “magic target” approach can cure cancer. “Magic bullet” can kill “magic target” MDSC. Paclitaxel hits both cancer cells and MDSCs [50], and AFP potentiates its direct cytotoxic and immunotherapy action [51]. Thapsigargin is a more potent toxin than paclitaxel. AFP-thapsigargin complex (ACT-902) depletes MDSCs and tumor-associated macrophages. In mice, chemotherapy using ACT-902 and AFP with paclitaxel demonstrated superior efficacy and safety compared to chemotherapy alone. ACT-902 has led to the complete regression of five out of six highly resistant to chemotherapy POP-92 xenografts by day seven of treatment with no further growth after this period in mice [52]. Or the AFP-maytansine conjugate combines both immunotherapy and targeted chemotherapy with undetectable bone marrow toxicity. It has shown 100% survival with no tumor re-growth after in the mice models [53]. AFP-toxin conjugates might pave a new road to the cancer cure [54-58]. On the other hand, unlike complexes, artificial conjugates have the risk of immune response to themselves. The neuroblastoma cells may re-express embryonal or fetal antigens, suggesting some reversion towards an earlier stage of differentiation, and they can incorporate AFP [59, 60]. AFP-maytansine conjugate can kill brain tumor cells and CSCs found in human brain tumors [61]. Glioblastoma is the most aggressive, malignant primary brain tumor in adults. Myeloid cells are critical regulators of immune and therapeutic responses to glioblastoma [62]. In the glioblastoma micro- environment, M-MDSCs represent the predominant subset [63]. M-MDSCs can be depleted by AFP-toxin conjugate [54]. It has been found that MDSCs account for approximately 30–50% of the tumor mass in gliomas. MDSCs are increased following conventional chemotherapy treatments [64]. Targeting MDSCs in combination with other therapies has shown promising therapeutic effects in brain cancer [65], and AFP-toxin drugs can be one of these therapies. III. O ral I nstead of I njectable “Let food be thy medicine, and let medicine be thy food.” Hippocrates MDSCs can be affected by ingredients from herbs and supplements. For example, withaferin A – a promising anti-cancer constituent of the Ayurvedic medicinal plant Withania somnifera –reduces MDSCs function [66]. Nevertheless, pregnant women should avoid Withania somnifera tonic as it may induce abortion at high doses [67]. In ancient Rome and Greece, women used silphium, an oral herbal contraceptive. This valuable herb is seen on a coin with a crab that once was a cancer disease name (Fig. 3).