In Vitro and In Vivo Studies of Non-Platinum-Based Halogenated Compounds as Potent Antitumor Agents for Natural Targeted Chemotherapy of Cancers

Abstract

Based on a molecular-mechanism-based anticancer drug discovery program enabled by an innovative femtomedicine approach, we have found a previously unknown class of non-platinum-based halogenated molecules (called FMD compounds) as potent antitumor agents for effective treatment of cancers. Here, we present in vitro and in vivo studies of the compounds for targeted chemotherapy of cervical, breast, ovarian, and lung cancers. Our results show that these FMD agents led to DNA damage, cell cycle arrest in the S phase, and apoptosis in cancer cells. We also observed that such a FMD compound caused an increase of reduced glutathione (GSH, an endogenous antioxidant) levels in human normal cells, while it largely depleted GSH in cancer cells. We correspondingly found that these FMD agents exhibited no or little toxicity toward normal cells/tissues, while causing significant cytotoxicity against cancer cells, as well as suppression and delay in tumor growth in mouse xenograft models of cervical, ovarian, breast and lung cancers. These compounds are therefore a previously undiscovered class of potent antitumor agents that can be translated into clinical trials for natural targeted chemotherapy of multiple cancers.

In Vitro and In Vivo Studies of a New Class of Anticancer Molecules for Targeted Radiotherapy of Cancer

“…Details on all the chemicals and reagents used in this study have been given previously (26). FMD-nX-DABs have excellent solubility of >40 mmol/L in ethanol (EtOH) and limited solubility ranging from 0.1 to 10 mmol/L in MEM (cell culture medium).…”

“…The details have been given previously (24)(25)(26). Briefly, cells were plated at a density of 7 Â 10 3 cells/well in 96-well plates.…”

“…Indeed, our studies have led to the development of novel cisplatin-based combination therapies that could significantly improve the therapeutic efficacy of cisplatin against human ovarian, cervical, and lung cancers (25). On the basis of our new understanding of differential intracellular environments between normal and cancerous cells, we have also discovered a new family of non-platinum-based molecules (called FMD molecules) that selectively kill cancer cells and protect normal cells, effective for targeted chemotherapy of multiple cancers (26).…”

“…An advantage of these FMD compounds over cisplatin and XdUs is that the DET reaction of FMDs is sufficiently effective, but they are far less toxic due to the absence of the heavy metal (Pt). Such FMD compounds alone have shown highly desirable targeting properties as antitumor agents for targeted chemotherapy of multiple types of cancer (26). Moreover, the DET reaction with an FMD molecule will be more effective in the microenvironment of tumor due to its hypoxia, which reduces the competitive attachment of e pre À to oxygen.…”

“…The newly discovered FMD compounds, such as 4,5-dichloro/dibromo/diiodo-1,2-diaminobenzene (benzenediamine/phenylenediamine) and 4(3)-chloro/bromo/iodo-1,2-diaminobenzene (benzenediamine/phenylenediamine; shortened as FMD-nX-DABs or B(NH 2 ) 2 X n , with X ¼ Cl, Br, or I and n ¼ 1, 2), act essentially as cisplatin analogues, whose molecular structures were reported previously (26). They are expected to be highly effective in DET reactions, with either weakly bound electrons intrinsic in the more reductive intracellular environment of abnormal (cancer) cells or ultrashort-lived e pre À produced by IR of biologic systems.…”