1. 1 Features & Advantagego
  2. 2 Differences go
  3. 3 Mechanismgo
  4. 4 Anti- tumor effect go
> Features & Advantage
Identification Kml001 (Kominox)
Chemicals name Sodium metaarsenite
Molecular formula NaAsO2
Molecular weight 129.9 g/mol
Purity > 99.8%
Solubility at water > 98 %
Biosorb rate more then 94.5%
Kominox is an arsenic-based new oral drug. There might be AsO2- ion in drinking water, sea weeds and plants. Compared to arsenic oxides such as As2O3, Kominox showed excellent tolerability. Kominox exerts anticancer activity and cancer pain-relieving efficacy by regulating gene expression and signal pathways in human body. The effectiveness is being verified in several non-clinical or clinical studies.

Arsenic as a chemical element (symbol As) occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. Arsenic trioxide (As2O3) can be generated via routine processing of arsenic compounds including the oxidation (combustion) of arsenic and arsenic-containing minerals in air.

2 As2S3 (orpiment)+ 9 O2 → 2 As2O3 + 6 SO2

Although As2O3 (or As2O6) was developed and used as an anti-cancer therapeutic, it is not popular because of its severe toxicities.
> Differences

Kominox is a relatively safe drug with very high water solubility compared with arsenic trioxide.
According to X-ray crystallography data, these two materials have completely different molecular structures.

NaAsO2(KOMINOX) As2O3 (As4O6) (Arsenic trioxide)
Laboratory rat oral toxicity LD50 41.6 mg/kg 14.6 mg/kg

X-ray crystallographic data from Acta Cryst. (2004). C60, m215-m218
X-ray crystallographic data from P. Ballirano, A. Maras (2002). Refinement of the crystal structure of arsenolite, As2O3

> Mechanism
Breast cancer-free survival interval is determined by telomere DNA content (TC) in patients with breast tumors

Clinical Cancer Research (2007) 13(23): 037-7043
Telomere DNA Content Predicts Breast Cancer–Free Survival Interval

The set of all tumors (A) or invasive tumors only (B) was divided into two groups based on the low-TC and high-TC cutoff (200% of standard). Breast cancer- free survival interval (in y) is shown on the x axis, and the recurrence-free fraction is shown on the y axis. Subjects were censored at the time lost to follow-up. The log-rank test was used to test the significance (P) of the differences in the group’s survival intervals. n, number of subjects in each group.

Telomere shortening by Kominox Cell lines with shorter telomeres are more sensitive to Kominox

Clinical Cancer Research (2008) 14(14): 4593-4602

Fluorescence in situ hybridization (FISH) of metaphase chromosomes (DAPI blue) of PC-3 cells with all human telomere probes (red). Interphase nuclei are inserted into the top right corner of each photomicrograph and boxed with a blue line. Enlargements of individual chromosomes that are indicated in the individual photomicrographs as a white box. Treatments and time points are indicated on top. Fluorescence in situ hybridization for the lung cancer cell line H1838. Enlargements of individual chromosomes. Magnification, ×100 (metaphases and interphases).

Presentation of telomere restriction fragment (TRF) lengths ± SD as determined by Southern blot for the six cell lines. Spearman rank correlation coefficient analysis for fold ratio of mean IC50 values versus telomere length in 11 cell lines(PC-3 (prostate), DU145 (prostate), MCF7 parental (breast), MCF7 wt hTERT, MCF7 mt hTERT, A2780 (ovarian), A2780cis, HEK293T (embryonic kidney), Saos-2 (osteosarcoma, ALT), HT29 (colon) and H1838 (lung)). A highly significant correlation coefficient of r2= 0.9 was found for short telomere length and low IC50 values/high cytotoxicty.

Interaction between Kominox and telomeres Anti-cancer mechanism of Kominox

Kml001 binding to (TTAGGG)3 by MALDI

Clinical Cancer Research (2008) 14(14): 4593-4602

Modified after Blackburn EH, Nature 2000:408:53-56

Kominox binding to (TTAGGG)3 by high-resolution matrix-assisted laser desorption/ionization (MALDI). Single-stranded 5´-(TTAGGG)3-3´ oligonucleotide was incubated with and without Kominox for 24 h in an aqueous solution at 37℃ and a molar ratio of 1:10. A shift to the right (blue curve) in the order of 130 (molecular weight of Kominox) is observed in the sample treated with Kominox, suggesting that Kominox can directly bind to telomeres.

By combining with telomere directly, Kominox induces fast loss of telomere and this causes senescence and apoptosis of cancer cells.
> Mechanism
Effects of Kominox on cancer stem cells - FACS Effects of cancer stem cells- Clonogenic assay

Kml001 effect on the DCV SP profile for DU145/Pac200. The gated SP is identified based on the PgP inhibitor Verapamil (VP). In the presence of Kml001 the gated SP is reduced by 38%.

Growth of the unsorted cells, SP – and the SP + fraction from the prostate cancer cell line DU145/Pac200 and DU145/Doc50

Mol Pharmacol . August 2012 82:310-321

Effect of Kominox on the DCV SP profile for DU145/Pac200. The gated SP is identified based on the PgP inhibitor Verapamil (VP). In the presence of Kominox the gated SP is reduced by 38%.

Growth of the prostate cancer cell lines DU145/Pac200 comparing the unsorted cells, SP – and the SP + fraction from the prostate cancer cell line DU145/Pac200 and DU145/Doc50 in the clonogenic assay shown as average number of colonies formed in the untreated versus Kml001 treated cell lines. Kml001 effects especially the CSC (SP+) population in the clonogenic assay.
> Anti- tumor effect

Antitumor effect of Kominox in a xenograft nude mouse model

Anti-tumor effects of Kominox in a xengraft nude mouse model.
The effect of Kominox on change of tumor volume of HuCCT-1(Human Cholangiocarcinoma) cells. The values represent means ± S.E.

Antitumor effect of Kominox in HuCCT-1 xenograft nude mouse model (After 28days)
A: Control, B: Kominox 3.5mg/kg, C: Kominox 7mg/kg, D: Gemcitabine-HCl 3.5mg/kg