<i>In Vitro</i> and <i>In Vivo</i> Studies of a New Class of Anticancer Molecules for Targeted Radiotherapy of Cancer

Wang, Chun Rong; Mahmood, Javed; Zhang, Qin Rong; Vedadi, Ali; Warrington, Jenny; Ou, Ning; Bristow, Robert G.; Jaffray, David A.; Lü, Qing

doi:10.1158/1535-7163.mct-15-0862

Cited by 12 publications

(24 citation statements)

References 29 publications

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“…It remains to be investigated whether reactive oxygen species may be involved in the combinational treatment of X-ray and radiotherapy (21,22). We also found that the cytotoxicity of X-ray irradiation was also enhanced by sodium ascorbate and chlorogenic acid, well-known antioxidants.…”

Section: Discussionmentioning

confidence: 81%

Augmentation of Neurotoxicity of Anticancer Drugs by X-Ray Irradiation

Nakaya

Sakagami

Koga‐Ogawa

et al. 2020

In Vivo

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Background: In order to investigate the combination effect of anticancer drugs and X-ray irradiation on neurotoxic side-effects (neurotoxicity), a method that provides homogeneously X-ray-irradiated cells was newly established. Materials and Methods: PC12 cell suspension was irradiated by X-ray (0.5 Gy) in serum-supplemented medium, immediately inoculated into 96-microwell plates and incubated overnight. The medium was replaced with fresh serum-depleted medium containing 50 ng/ml nerve growth factor to induce differentiation toward nerve-like cells with characteristic neurites according to the overlay method without changing the medium. The differentiated cells were treated by anticancer drugs as well as antioxidants, oxaliplatin or bortezomib, and the viable cell number was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide method. Results: Antioxidants and anticancer drugs were cytotoxic to differentiating PC12 cells. Combination of anticancer drugs and X-ray irradiation slightly reduced cell viability. Conclusion: The present 'population irradiation method' may be useful for the investigation of the combination effect of X-ray irradiation and any pharmaceutical drug. X-Rays are used for many purposes in various fields. This includes the visualization of the distribution and therapeutic effects of drugs by X-ray computed tomography (1); the assessment of chemical element changes by energy dispersive X-ray spectrometry (2); the analysis of crystal structure by Xray diffraction (3); the analysis of oral mucosal distribution of trace metal elements by X-ray fluorescence with synchrotron radiation and particle-induced X-ray emission, and the estimation of chemical states of elements by X-ray absorption fine-structure analysis (4); the visual inspection of passenger baggage in airports by X-ray images (5); and therapeutic applications in medicine (6). Radiation, such as X-rays, and drugs, are reported to exert dose-dependent biphasic effects (7). X-Ray irradiation has been reported to stimulate the production of reactive oxygen-species such as superoxide and nitrite (8, 9), the secretion of Fas ligand (10), the accumulation of cells in the G 2 +M phase in the cell cycle (11), and the shortening of telomeres (12). On the other hand, at lower doses of X-irradiation, beneficial effects (known as hormesis) can be induced. For example, Xirradiation at 10 mGy (but not 50 or 100 mGy) reduced the frequency of micronucleated cells in human lymphocytes to below the spontaneous level (13). Recently, we discovered that among anticancer drugs, platinum preparations (cisplatin, carboplatin, oxaliplatin) and proteasome inhibitor bortezomib showed potent cytotoxicity not only against normal oral keratinocytes (14) but also against PC12 nerve-like cells (Iijima et al., unpublished data). The neurotoxicity of anticancer agents and X-ray irradiation is a recent research topic in today's aging society. In the present study, we investigated whether cytotoxic doses of X-ray irradiation further augment neurotoxicity...

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Section: Discussionmentioning

confidence: 81%

Augmentation of Neurotoxicity of Anticancer Drugs by X-Ray Irradiation

Nakaya

Sakagami

Koga‐Ogawa

et al. 2020

In Vivo

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“…Exogenous halogenated aromatic ring compounds as neutral small molecules that can freely diffuse across membrane will be potent anti-pathogen agents. Here we present a new molecular mechanism of action (MOA) of a class of halogenated aromatic drugs such as chloroquine and hydroxychloroquine (HCQ), which have been a current focus for experimental treatment of COVID-19 [ 66 , 67 , 68 ] and more potent di-amino, di-halogen aromatic ring molecules [termed femtomedicine compounds, FMDs], which have exhibited excellent targeted chemotherapy of multiple cancers [ 69 , 70 , 71 ]. These drugs or candidates are promising for effective treatments of COVID-19, cancer and other diseases.…”

Section: Halogenated Aromatic Drugs As Repurposed Drugsmentioning

confidence: 99%

“…Here we propose a new molecular MOA of halogen-containing aromatic ring drugs represented by AXs, including HCQ and chloroquine, and a family of FMD halogenated compounds [ 69 , 70 , 71 ]. Here A is a quine ring system and X = Cl for HCQ and chloroquine, whereas A is an aromatic ring coupled to two NH 2 groups at ortho positions [A = B(NH 2 ) 2 ] and X = Cl n or Br n or I n with n = 1,2 for FMD compounds such as 4,5-dichloro/dibromo/diiodo-1,2-diaminobenzene and 4(5)-chloro/bromo/iodo-1,2-diaminobenzene [ 69 , 70 ]. We propose that these molecules are highly effective for DET reactions and their action is quite similar to the formation of endogenous RHS in the phagosome.…”

Section: Halogenated Aromatic Drugs As Repurposed Drugsmentioning

confidence: 99%

Reaction Cycles of Halogen Species in the Immune Defense: Implications for Human Health and Diseases and the Pathology and Treatment of COVID-19

Lü

2020

Cells

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There is no vaccine or specific antiviral treatment for COVID-19, which is causing a global pandemic. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. Without this understanding, it is challenging to discover a successful treatment to be approved for clinical use. This paper addresses several key biological processes of reactive oxygen, halogen and nitrogen species (ROS, RHS and RNS) that play crucial physiological roles in organisms from plants to humans. These include why superoxide dismutases, the enzymes to catalyze the formation of H2O2, are required for protecting ROS-induced injury in cell metabolism, why the amount of ROS/RNS produced by ionizing radiation at clinically relevant doses is ~1000 fold lower than the endogenous ROS/RNS level routinely produced in the cell and why a low level of endogenous RHS plays a crucial role in phagocytosis for immune defense. Herein we propose a plausible amplification mechanism in immune defense: ozone-depleting-like halogen cyclic reactions enhancing RHS effects are responsible for all the mentioned physiological functions, which are activated by H2O2 and deactivated by NO signaling molecule. Our results show that the reaction cycles can be repeated thousands of times and amplify the RHS pathogen-killing (defense) effects by 100,000 fold in phagocytosis, resembling the cyclic ozone-depleting reactions in the stratosphere. It is unraveled that H2O2 is a required protective signaling molecule (angel) in the defense system for human health and its dysfunction can cause many diseases or conditions such as autoimmune disorders, aging and cancer. We also identify a class of potent drugs for effective treatment of invading pathogens such as HIV and SARS-CoV-2 (COVID-19), cancer and other diseases, and provide a molecular mechanism of action of the drugs or candidates.

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“…[39] By using laser or high-energye lectron pulses lowenergy electron-induced reactions in DNA modelc ompounds and the effect of radiosensitizers can be studied in aqueous solution. [24,40,41] Small model compounds for DNA such as nucleosidesa nd nucleotides and buildingb locks such as DNA nucleobases, sugar and phosphate can be studied under well-definedc onditions either in the gas phase or as thin films in the condensed phase. The targetm olecules are irradiated in high-or ultrahigh vacuum with low-energy electrons of well-definede nergy (with an energy resolutiono ftypically 100 meV), and the formed parent anions and fragmentation products can be detected using mass spectrometry.N umerous experimentsh ave been reported, which are summarizede lsewhere.…”

Section: Experimental Challengesmentioning

confidence: 99%

“…By UV/Vis absorption spectroscopy and surface‐enhanced Raman scattering (SERS) the decomposition of molecules can be monitored and decomposition rates determined . By using laser or high‐energy electron pulses low‐energy electron‐induced reactions in DNA model compounds and the effect of radiosensitizers can be studied in aqueous solution …”

Section: Experimental Challengesmentioning

confidence: 99%

The Physico‐Chemical Basis of DNA Radiosensitization: Implications for Cancer Radiation Therapy

Schürmann

Vogel

Ebel

et al. 2018

Chemistry A European J

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High-energy radiation is used in combination with radiosensitizing therapeutics to treat cancer. The most common radiosensitizers are halogenated nucleosides and cisplatin derivatives, and recently also metal nanoparticles have been suggested as potential radiosensitizing agents. The radiosensitizing action of these compounds can at least partly be ascribed to an enhanced reactivity towards secondary low-energy electrons generated along the radiation track of the high-energy primary radiation, or to an additional emission of secondary reactive electrons close to the tumor tissue. This is referred to as physico-chemical radiosensitization. In this Concept article we present current experimental methods used to study fundamental processes of physico-chemical radiosensitization and discuss the most relevant classes of radiosensitizers. Open questions in the current discussions are identified and future directions outlined, which can lead to optimized treatment protocols or even novel therapeutic concepts.

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

Cited by 12 publications

References 29 publications

Augmentation of Neurotoxicity of Anticancer Drugs by X-Ray Irradiation

Augmentation of Neurotoxicity of Anticancer Drugs by X-Ray Irradiation

Reaction Cycles of Halogen Species in the Immune Defense: Implications for Human Health and Diseases and the Pathology and Treatment of COVID-19

The Physico‐Chemical Basis of DNA Radiosensitization: Implications for Cancer Radiation Therapy

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