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

Lu QB, Zhang QR, Ou N, Wang CR, Warrington J - EBioMedicine (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada ; Departments of Biology and Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

Cell cycle analysis by flow cytometry of human cervical cancer cells (ME-180) treated by FMD-2Br-DAB for 48 h. The cell cycle histograms contain statistics giving percentages for G1, S, and G2 phases of the cycle, analyzed using a FlowJo software. The fits to the DNA histograms of the samples were performed by the Watson model.A: ME-180 cancer cells in control.B: ME-180 cancer cells treated by 100 μM FMD.C: Percentages of cell-cycle phases versus FMD concentration.
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f0030: Cell cycle analysis by flow cytometry of human cervical cancer cells (ME-180) treated by FMD-2Br-DAB for 48 h. The cell cycle histograms contain statistics giving percentages for G1, S, and G2 phases of the cycle, analyzed using a FlowJo software. The fits to the DNA histograms of the samples were performed by the Watson model.A: ME-180 cancer cells in control.B: ME-180 cancer cells treated by 100 μM FMD.C: Percentages of cell-cycle phases versus FMD concentration.

Mentions: Using the same APO-BrdU™ TUNEL Assay Kit (Invitrogen), we performed cell cycle analysis of human cervical cancer cells (ME-180) treated by FMD-2Br-DAB at 0 and 100 μM for 48 h. The results are shown in Fig. 5. The cell cycle histograms contain statistics giving percentages for G1, S, and G2 phases of the cycle. It was observed that the treatment of the 50 μM FMD compound led to a slight decrease in the percentage of G1 phase from ~ 33% to ~ 30%, a decrease in the percentage of G2 phase from ~ 24% to ~ 13% and an increase in the percentage of S phase from ~ 36% to ~ 54%. These results show that the FMD agent induced DNA damage and blocked the cells in the DNA synthesis (S phase) (P < 0.005), in good agreement with the observed DNA damage caused by the FMD (Fig. 3). These results indicate that the FMD-induced DNA damage activated cell-cycle checkpoints, which induced a S-phase arrest. This is consistent with the generally accepted notion that DNA damage leads to cell cycle arrest; when repair of damage is difficult or incomplete, the cells undergo apoptosis. Thus, the induced DNA damage is closely associated with activation of cell-cycle checkpoints and apoptosis.


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

Lu QB, Zhang QR, Ou N, Wang CR, Warrington J - EBioMedicine (2015)

Cell cycle analysis by flow cytometry of human cervical cancer cells (ME-180) treated by FMD-2Br-DAB for 48 h. The cell cycle histograms contain statistics giving percentages for G1, S, and G2 phases of the cycle, analyzed using a FlowJo software. The fits to the DNA histograms of the samples were performed by the Watson model.A: ME-180 cancer cells in control.B: ME-180 cancer cells treated by 100 μM FMD.C: Percentages of cell-cycle phases versus FMD concentration.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4551467&req=5

f0030: Cell cycle analysis by flow cytometry of human cervical cancer cells (ME-180) treated by FMD-2Br-DAB for 48 h. The cell cycle histograms contain statistics giving percentages for G1, S, and G2 phases of the cycle, analyzed using a FlowJo software. The fits to the DNA histograms of the samples were performed by the Watson model.A: ME-180 cancer cells in control.B: ME-180 cancer cells treated by 100 μM FMD.C: Percentages of cell-cycle phases versus FMD concentration.
Mentions: Using the same APO-BrdU™ TUNEL Assay Kit (Invitrogen), we performed cell cycle analysis of human cervical cancer cells (ME-180) treated by FMD-2Br-DAB at 0 and 100 μM for 48 h. The results are shown in Fig. 5. The cell cycle histograms contain statistics giving percentages for G1, S, and G2 phases of the cycle. It was observed that the treatment of the 50 μM FMD compound led to a slight decrease in the percentage of G1 phase from ~ 33% to ~ 30%, a decrease in the percentage of G2 phase from ~ 24% to ~ 13% and an increase in the percentage of S phase from ~ 36% to ~ 54%. These results show that the FMD agent induced DNA damage and blocked the cells in the DNA synthesis (S phase) (P < 0.005), in good agreement with the observed DNA damage caused by the FMD (Fig. 3). These results indicate that the FMD-induced DNA damage activated cell-cycle checkpoints, which induced a S-phase arrest. This is consistent with the generally accepted notion that DNA damage leads to cell cycle arrest; when repair of damage is difficult or incomplete, the cells undergo apoptosis. Thus, the induced DNA damage is closely associated with activation of cell-cycle checkpoints and apoptosis.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada ; Departments of Biology and Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada.

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.

No MeSH data available.


Related in: MedlinePlus