Electron transfer-based combination therapy of cisplatin with tetramethyl- p -phenylenediamine for ovarian, cervical, and lung cancers

Abstract

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...

Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin

“…Chemotherapy is among the pilot methods of treatment for cancer patients (Florea and Büsselberg 2011;Luo et al 2012;Raschi and De Ponti 2012). Several investigators have reported that anticancer agents have been utilized for the chemotherapy of various cancers such as sarcoma small cell lung cancer, ovarian cancer, lymphomas, germ cell tumors, and CNS disability (Iwata et al 2012;Lee et al 2012a, b;Rinne et al 2012), but they have also been implicated in causing various kinds of toxicity after treatment in cancer patients measured as adverse effects (Dharap et al 2005;Erkurt et al 2008).…”

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

“…2 and Supplementary Fig. S1, we further measured DNA DSBs in cancer cells treated by FMD-2Br-DAB in combination with IR (225 kV X-rays), using the HCS DNA Damage (gH2AX) Kit (24)(25)(26). Figure 3 shows the fluorescence images of cervical cancer (ME-180) cells with/without the treatment of 25/200 mmol/L FMD and the yield of DNA DSBs detected by gH2AX foci with various X-ray doses, respectively.…”

“…At 12 hours after X-ray irradiation, the cells were fixed and stained. Following the detailed protocol provided by the manufacturer, we performed the HCS DNA Damage Assay of the treated cells, as described previously (24)(25)(26). The images of cells were acquired with a Nikon Eclipse TS100 fluorescence microscope; quantitative analyses of activated gH2AX (DNA DBS yield) in the cells were performed using an Image J software.…”

“…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.…”

“…Our mechanistic studies in FMD (12)(13)(14)(15)(16)(17)(18)(19)22) provide remarkable opportunities to improve the therapies of existing drugs and to develop new effective drugs. 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).…”