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    • We have now successfully found a previously unknown family o

    2018-10-25

    We have now successfully found a previously unknown family of non-platinum-based anticancer compounds (called FMD compounds) as potent antitumor agents for natural targeted chemotherapy without the need of using an antibody to bind to cancer cells. Upon entering normal and abnormal (cancer) cells, the FMD compounds, which are highly oxidizing agents, have effects just opposite to those induced by antioxidants and are capable of generating the anti-cancer effects on cancer cdc42 pathway while having minimal toxicity toward normal cells. They are highly reactive with weakly-bound electrons rich in the more reduced intracellular/intranuclear environment of cancer cells. In contrast, the FMDs are much less toxic toward normal cells due to the lack of a reduced intracellular/intranuclear environment in normal cells. Therefore FMDs have no or low systemic or acute toxicity in the body. They are effective anti-cancer agents that can preferentially kill cancer cells and are therefore useful for natural targeted chemotherapy of cancer and potentially other disorders treatable by chemotherapy. The FMDs are superior to cisplatin, which has poor target selectivity and is highly toxic due to the containing of the heavy metal (Pt) readily binding to proteins in kidney (Townsend and Hanigan, 2002; Zhang et al., 2006), though cisplatin has also generally stronger toxicity against cancer cells. To the best our knowledge, no previous studies showing considerable toxicity of our identified FMD compounds have been reported in the literature. A previous study by Yu et al. (2008) showed that all six non-halogenated and halogenated (chlorinated) phenylenediamines (PD) as dye precursors used to manufacture hair dyes are not toxic/mutagenic in Salmonella typhimurium TA 102 bacteria or skin keratinocyte cells, and do not cause DNA cleavage in ΦX 174 phage DNA. Their phototoxicity test in skin cells showed that without light irradiation, all the PD compounds are not toxic to the keratinocytes up to 1000μM; only at an extremely high PD concentration (1000μM) and with extensive exposure to light irradiation (at a large light dose of 3.3J/cm2 of UVA and 6.3J/cm2 of visible light), two chlorinated PDs and two non-chlorinated PDs show modest phototoxicity. However, the phototoxicity is a subject that has no direct relevance to the work reported in our present manuscript. In the present studies, our in vitro results from cell viability measurements show that the FMD compounds significantly enhanced the killing of both cisplatin-sensitive cancer cells and cisplatin-resistant cancer cells. Furthermore, large enhancements in DNA damage and apoptosis in the treated cancer cells but no normal cells were also observed. Our cell cycle measurements also correspondingly show that the FMD compounds significantly inhibited DNA synthesis in the cell cycle, resulting in cell arrest in the S phase. We also found that the FMD compounds exhibited little toxicity toward human normal cells with measured IC50 values ≥200μM, in contrast to the clinically widely-used but highly-toxic cisplatin with IC50s ≤10μM for 72-hr incubation. Very interestingly, we also observed the marked difference in modifying the levels of the reduced glutathione (GSH, an endogenous antioxidant) in normal and cancer cells. A FMD up to 100μM caused a significant increase of the GSH level in normal cells, while it largely depleted the GSH in cancer cells. Although further studies as to how the FMD compound enhances the GSH level in normal cells are needed, these results indicate a selective strong reaction between the FMD and the GSH within cancer cells and to kill the latter. Thus, these FMD agents are ideal potent anticancer agents. Correspondingly, our in vivo results have clearly confirmed that FMD-2Br-DAB and FMD-2I-DAB as exemplary FMD compounds exhibited no or minimal toxicity in mice, no overall physical toxicity and no acute toxicity (no hepatotoxicity, no nephrotoxicity, and no changes in electrolytes). These results are in excellent agreement with the in vitro results observed in human normal cells. Furthermore, the in vivo results from the xenograft mouse tumor models of human cervical cancer, lung cancer, breast cancer and ovarian cancer exhibited significant tumor growth inhibition and regrowth delay due to the anti-cancer effect of the FMD compounds. These results demonstrate that the FMDs are indeed potent anti-cancer agents for natural targeted chemotherapy. Given that only a small dose (5 or 7mg/kg) of the FMDs were used in the present experiment and that the FMDs showed little or no toxicity at much higher doses in vitro, it is reasonably expected that these results can be extrapolated to larger doses or more frequent treatments so that a maximal therapeutic efficacy can be achieved.