The platinum-based chemotherapy is the standard treatment for several types of cancer. However, cancer cells often become refractory with time and most patients with serious cancers die of drug resistance. Recently, we have discovered a unique dissociative electron-transfer mechanism of action of cisplatin, the first and most widely used platinum-based anticancer drug. Here, we show that the combination of cisplatin with an exemplary biological electron donor, N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD), may overcome the resistance of cancer cells to cisplatin. Our steady-state absorption and fluorescence spectroscopic measurements confirm the effective dissociative electron-transfer reaction between TMPD and cisplatin. More significantly, we found that the combination of 100 μM TMPD with cisplatin enhances double-strand breaks of plasmid DNA by a factor of approximately 3.5 and dramatically reduces the viability of cisplatin-sensitive human cervical (HeLa) cancer cells and highly cisplatin-resistant human ovarian (NIH:OVCAR-3) and lung (A549) cancer cells. Furthermore, this combination enhances apoptosis and DNA fragmentation by factors of 2-5 compared with cisplatin alone. These results demonstrate that this combination treatment not only results in a strong synergetic effect, but also makes resistant cancer cells sensitive to cisplatin. Because cisplatin is the cornerstone agent for the treatment of a variety of human cancers (including testicular, ovarian, cervical, bladder, head/neck, and lung cancers), our results show both the potential to improve platinum-based chemotherapy of various human cancers and the promise of femtomedicine as an emerging frontier in advancing cancer therapy.biophysics | physical biology | chemical biology | biological chemistry E lectron-transfer reactions play key roles in diverse processes in chemistry, physics, and biology, ranging from photo-induced reactions (1, 2), electron tunneling in proteins (3), and electron transport in DNA (4) to the ozone hole formation (5) and reductive DNA damage (6, 7). Electron-transfer reactions in molecular systems have therefore been the subject of intense experimental and theoretical studies. Following the pioneering contribution of Zewail (8), the advent of femtosecond time-resolved laser spectroscopy (fs-TRLS; 1 fs ¼ 10 −15 s) provided an unprecedented capacity in techniques of observing molecular reactions, including electron transfer. Its application to the study of chemical and biological systems led to the birth of new scientific subfields: femtochemistry and femtobiology (8). Recently, Lu (9) further proposed that integrating ultrafast laser techniques with biomedical methods to advance fundamental understandings and treatments of major human diseases might lead to the opening of a new frontier called femtomedicine. Regarding the latter, we have recently unraveled unique dissociative electron-transfer (DET) mechanisms of reductive DNA damage (6, 7) and several anticancer agents for radiotherapy and chemotherapy (10)(11)(12)(13)(14...

There is a compelling need to develop anticancer therapies that target cancer cells and tissues. Arising from innovative femtomedicine studies, a new class of non-platinum-based halogenated molecules (called FMD molecules) that selectively kill cancer cells and protect normal cells in treatments of multiple cancers has been discovered. This article reports the first observation of the radiosensitizing effects of such compounds in combination with ionizing radiation for targeted radiotherapy of a variety of cancers. We present in vitro and in vivo studies focused on combination with radiotherapy of cervical, ovarian, head and neck, and lung cancers. Our results demonstrate that treatments of various cancer