Dose Response of MTLN3 Cells to Serial Dilutions of Arsenic Trioxide and Ionizing Radiation

Abstract

ᮀ MTLn3 cells derived from mouse mammary epithelium are known to be highly malignant and are resistant to both radio-and chemo-therapy. We exposed MTLn3 cells to various doses of inorganic Arsenic trioxide (As 2 O 3 ) in combination with ionizing radiation. Cells were treated with a series of As 2 O 3 concentrations ranging from 20 µM to 1.22 nM for 8 hour, 24 hour and 48 hour periods. Post-treated cell proliferation was quantified by measuring mitochondrial activity and DNA analysis. Cells exposed to radiation and As 2 O 3 at concentration greater than 1.25 µM showed apoptosis and radiations alone treated cells were statistically not different from the control. Hormesis was observed for As 2 O 3 concentrations in the range of 0.078 µM to 0.625 µM while the combined chemo and radiation treatments of the cells did not affect the hormetic effect. We have demonstrated that As 2 O 3 (in the presence and absence of ionizing radiation) in specific low concentrations induced apoptosis in the otherwise chemoresistant cancer cells. This low concentrationmediated cell death is immediately followed by a surge in cell survival. Low dosing dosimetry is highly desirable in metronomic therapy however, it has a narrow window since necrosis, hormesis, apoptosis and other dose-dependent biological processes take place in this region. Further quantifiable dosimetry is highly desired for routine clinical practice.

Dual effects of arsenic trioxide on tumor cells and the potential underlying mechanisms

“…The hormesis of As 2 O 3 has also been demonstrated by other research groups ( 10 , 25 ). It was reported that a low dose of As 2 O 3 could stimulate osteoblast and MTLn3 cell proliferation ( 10 ). Wang et al ( 27 ) demonstrated that hERG protein expression is associated with tumor-cell proliferation and cancer development.…”

Nonlinear Effects of Nanoparticles: Biological Variability from Hormetic Doses, Small Particle Sizes, and Dynamic Adaptive Interactions

“…In that case, looking to a very low dose range might reveal a beneficial hormetic dose range for their adaptation-stimulating effects in most organisms. Thus, it makes sense to look for hormesis at extremely low doses of bulk form arsenic (Raja et al, 2013) and perhaps even lower doses of nano-arsenic trioxide (Ahn et al, 2013). Other nanomaterials such as nano-calcium hydroxyapatite may be largely benign across a wider range of dose levels (Zhou and Lee, 2011) and/or can safely deliver nano-forms of less toxic agents for greater bioavailability and clinical benefit than reliance on more toxic bulk form drugs (Chun et al, 2012;Joshi and Muller, 2009;Koning and Krijger, 2007;Lanao et al, 2007;Moulari et al, 2013;Zhao and Feng, 2010).…”

Nanoparticle Characterization of Traditional Homeopathically- Manufactured Gelsemium sempervirens Medicines and Placebo Controls

“…Variability in particle surface properties and materials involved in NP stabilization might contribute to previous findings of variability over time in UV-vis findings on HMs versus controls [85,169,170]. Finally, subsequent research should also evaluate the nanostructure and surface stability characteristics of HMs as correlates of their biological activity [26,27,31,32,132,133,[171][172][173][174] in comparison with succussed and unsuccussed controls [65,78,141,175]. Prior research has demonstrated low-dose hormetic effects triggered in recipient organisms by NPs of various source materials [132][133][134]149,171].…”

“…Finally, subsequent research should also evaluate the nanostructure and surface stability characteristics of HMs as correlates of their biological activity [26,27,31,32,132,133,[171][172][173][174] in comparison with succussed and unsuccussed controls [65,78,141,175]. Prior research has demonstrated low-dose hormetic effects triggered in recipient organisms by NPs of various source materials [132][133][134]149,171]. Consequently, examining NPs in various HMs, especially at higher homeopathic potencies such as 30C and 200C (i.e., low conventional doses), for these types of lowdose-dependent, nonlinear dose-response patterns, rather than direct pharmacological ligand-receptor effects, merits further investigation [31,131,142,176].…”