In Vitro and In Vivo Studies of Non-Platinum-Based …

Highlights

Femtomedicine may accelerate drug discovery for effective treatment of cancer.

A previously undiscovered class of non-platinum-based halogenated compounds is found to have potent antitumor effects.

FMD agents can be used for natural targeted chemotherapy of multiple types of cancer while inducing minimal toxicity.

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.

The conquest of cancer continues to pose great challenges to medical science (Reese, 1995andVarmus, 2006; Alberts, 2011andWatson, 2013). There is a compelling need for innovative cancer research integrating biomedical sciences with new technology in order to ultimately conquer cancer. Femtosecond (fs) (1fs=1015s) time-resolved laser spectroscopy (fs-TRLS) is a direct technique to visualize molecular reactions in real time. Its application to chemical and biological systems gave birth to the fields of femtochemistry and femtobiology, with the pioneering contribution of Zewail (2000). Further, femtomedicine (FMD), which fuses ultrafast laser spectroscopic techniques with biomedical sciences, was recently coined to advance fundamental understanding and therapies of human diseases notably cancer (Wang et al., 2009, Lu, 2010aandNguyen et al., 2011).

In particular, we proposed that dissociative-electron-transfer (DET) reactions may be exploited to improve cancer therapy (Lu, 2010aandLuo et al., 2012). Prior to our studies in FMD, it had strikingly been found that electron-induced dissociation of halogenated molecules were enhanced by up to 30,000 times with the presence of polar molecules such as NH3 and H2O, and a DET mechanism involving a prehydrated electron (epre) trapped in polar media was proposed to explain the results (Lu and Madey, 1999andLu, 2010b). Employing fs-TRLS, we demonstrated that epre in liquid water has a lifetime of about 500fs and is a weakly-bound excited state of the hydrated/solvated electron (Wang et al., 2008). We further discovered that the epre plays a key role in causing the biological effects of ionizing radiation: its ultrafast DET reaction leads to chemical bond breaks at the guanine base (Wang et al., 2009) and strand breaks in DNA (Nguyen et al., 2011). Our findings challenged the conventional notion that damage to the genome by ionizing radiation is mainly oxidative, induced by oxidizing OH, and might lead to improved strategies for radiotherapy of cancer (Lu, 2010a).

We have also discovered the DET mechanism of cisplatin (Lu, 2007andLu et al., 2007). Platinum compounds as a class of antitumor agents were discovered unexpectedly by the biophysicist Rosenberg et al., 1965andRosenberg et al., 1969. Despite its severe toxicity (Reese, 1995), cisplatin is a widely-used drug in the treatment of a variety of cancer, including ovarian, testicular, cervical, bladder, lung, head and neck, lymphomas, and brain cancers, both as chemotherapy alone and in combination with radiotherapy. Although platinum compounds are well-known DNA-attacking agents, their precise molecular mechanism of action remained elusive until recently. Through fs-TRLS studies, we found that cisplatin is very effective for the DET reaction with a weakly-bound electron, such as an ultrashort-lived epre produced by radiolysis of water (Lu, 2007):

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In Vitro and In Vivo Studies of Non-Platinum-Based ...