Chemoquiescence for Ideal Cancer Treatment and Prevention: Where Are We Now?

Napapan Kangwan,박종민,김은희,함기백 대한암예방학회 2014 Journal of cancer prevention Vol.19 No.2

Cellular quiescence is a state of reversible cell cycle arrest and is associated with a low metabolic state featured with decreased glycolysis, reduced translation rates, and activation of autophagy, fundamentally to provide nutrients for cell survival similar as seen in hybernation. As signal for quiescence, inactivating the target of rapamycin kinase and resulting reduced cell growth and biosynthesis are essential, but cellular quiescence is not always associated with reduced metabolism since it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. However, in cancer cells, overcoming intrinsic and acquired resistance of cancer stem or cancer dormancy cells to current clinical treatments can be reversed with the acquisition of chemoquiesence. The development of new drug combinations or strategy to treat the highly aggressive and metastatic cancers including relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas as well as gastrointestinal cancers which remain incurable in the clinic in spite of aggressive therapies, can be accelerated with the introduction of chemoquiescence agent, for which cancer stem cells or tumor dormancy should be eradicated or removed. Recently potential applications of metformin or chloroquine as well as the potential drugs under investigation such as proton pump inhibitor, sonic hedgehog inhibitor, and Akt inhibitor, are actively investigated in this field of chemoquiescence to achieve cancer cure far beyond those of chemoprevention. In this review article, the evolving concept of chemoquiescence or cancer dormancy will be introduced accompanied by a description of novel target drug development.

The Korean Society of Gastroenterology & SIDDS 2035 : Slide Session ;K-LG-06 : Lower GI Tract ; Inhibition of Sonic Hedgehog Pathway Prevent Colitis- Associated Cancer in Mice

( Napapan Kangwan ),( Eun Hee Kim ),( Yoon Jae Kim ),( Kwang Hyun Ko ),( Chang Il Kwon ),( Pil Won Park ),( Ki Baik Hahm ) 대한내과학회 2014 대한내과학회 추계학술발표논문집 Vol.2014 No.1

Background/aims: Colitis-associated cancer is the one of colorectal cancer that is associated with infi ammatory bowel diseases. Sonic hedgehog (SHH) signaling is essential to normal development of gastrointestinal (GI) tracts and it has been reported that aberrantly activated in GI cancers and regulated cancer stem cells fostering tumorigenesis. We have previously found that colitis-associated cancer can be controlled by anti-infi ammatory intervention and SHH pathway suppression inhibited proliferation of extrahepatic biliary tract cancer. Therefore, the aim of this study was to investigate the SHH pathway contributed to colitis-associated cancer development and the effi - cacy of SHH as preventive agents for colitis-associated cancer. Methods: C57BL/6 mice were induced by treatment with 3 mg/kg azoxymethane(AOM) followed by 2% DSS administration for 7 days. SHh inhibitors were treated by oral gavage and the mice were sacrifi ced at 3 and 16 weeks after AOM injection. Thecerulenin, cyclopamine, and itraconazole were used as SHH inhibitor. IL-6 and TNF-a gene expression were analyzed by RT-PCR. Expression of relative proteins was examined by immunohistochemistry and Western blot. Results: Treatment with SHH inhibitors were restored the length of colon and significantly decreased the number of aberrant crypt foci. In addition, SHH inhibitors were reduced tumor incidence and tumor multiplicity. In tumor tissue, SHH inhibitors not only decreased the infi ammation expression of IL-6, TNF-a, STAT3 and NFκB but also attenuated proliferation, while level of apoptosis markers cleaved caspase 3 was increased. Conclusion: Our results imply that the SHh inhibitor could be an effective strategy to prevent colitis-induced colorectal carcinogenesis through the plausible anti-infi ammatory and anti-tumorigenic actions.

Non-microbial approach for Helicobacter pylori as faster track to prevent gastric cancer than simple eradication.

Park, Sang-Ho,Kangwan, Napapan,Park, Jong-Min,Kim, Eun-Hee,Hahm, Ki Baik WJG Press 2013 World journal of gastroenterology Vol.19 No.47

<P>Although the International Agency for Research on Cancer declared Helicobacter pylori (H. pylori) as a definite human carcinogen in 1994, the Japanese Society for Helicobacter Research only recently (February 2013) adopted the position that H. pylori infection should be considered as an indication for either amelioration of chronic gastritis or for decreasing gastric cancer mortality. Japanese researchers have found that H. pylori eradication halts progressive mucosal damage and that successful eradication in patients with non-atrophic gastritis most likely prevents subsequent development of gastric cancer. However, those who have already developed atrophic gastritis/gastric atrophy retain potential risk factors for gastric cancer. Because chronic perpetuated progression of H. pylori-associated gastric inflammation is associated with increased morbidity culminating in gastric carcinogenesis, a non-microbial approach to treatment that provides long-term control of gastric inflammation through nutrients and other interventions may be an effective way to decrease this morbidity. This non-microbial approach might represent a new form of prerequisite 'rescue' therapy that provides a quicker path to the prevention of gastric cancer as compared to simple eradication.</P>

The Korean Society of Gastroenterology& SLDDS 2062 : Slide Session ; K-GIO-01 : GI Oncology ; Omega 3-Fatty Acids Prevent Tumor Developmentiin Helicobacter pylori-Infected Mice

( Eun Hee Kim ),( Young Min Han ),( Napapan Kangwan ),( Sung Pyo Hong ),( Kwang Hyun Ko ),( Ki Baik Hahm ) 대한내과학회 2014 대한내과학회 추계학술발표논문집 Vol.2014 No.1

Background: Helicobacter pylori ( H. pylori) infection has been well known in acute gastritis, chronic atrophic gastritis, peptic ulcers as well as gastric cancer. Although the benefi ts of ω3 polyunsaturated fatty acids (ω3-PUFA) in diverse clinical diseases has been reported to the amelioration against infi ammation and cancer, there is no convincing experimental evidence that the ω3-PUFAs can prevent H. pylori-induced infi ammatory responses and carcinogenesis. In this study, we investigated ω3-PUFA might prevent H. pylori-induced gastric injury, especially in fat-1 transgenic mice,which can generate ω3-PUFA due to overexpression of 6-desaturase, converting ω6 into ω3-PUFA. Methods: Wild-type C57BL/6 and fat-1 transgenic mice at 4 weeks were inoculated with H. pylori (Sidney strain 1), mice were treated proton pump inhibitor for higher H. pylori infection rate before inoculation. For the serial sacrifi ce study, stomachs from wild-type C57BL/6 and fat-1 transgenic mice at 16, 24, 32 and 45 weeks of age were harvested. Results: H. pylori infection induced the discoloration, surface destruction, ulcerative and erosive lesions, infi ltration of infi ammatory cells on H. pylori-infected mice. As anticipated, ω3-PUFA imposed signifi cant protection from H. pylori-induced gastritis as well as attenuated incidence of H. pylori-induced gastric tumorigenesis in vivo. The average number of tumors per mice was reduced (P<0.05) in fat-1 mice, with an average of 0.7 tumors per mouse compared with an average of 1.5 tumors per mouse in the wildtype C57BL/6 mice. ω3-PUFA also showed the signifi cant anti-infi ammatory effects on H. pylori-infected gastritis through inhibiting the mucosal damages, the expression of infi ammatory enzymes, cytokines and pathologic fi nding in H. pylori-infected mice. Conclusions: In conclusion, ω3-PUFA can be anticipating novel substance to impose both action of anti-infi ammation and anti-tumorigenesis against H. pylori infection.

Chemoquiescence with Molecular Targeted Ablation of Cancer Stem Cells in Gastrointestinal Cancers

Jong-Min Park,Young-Min Han,Migyeong Jeong,Eun Jin Go,Napapan Kangwan,Woo Sung Kim,Ki Baik Hahm Korean Society of Gastrointestinal Cancer 2016 Journal of digestive cancer reports Vol.4 No.1

The abundance of multi-drug resistance ATPase binding cassette and deranged self-renewal pathways shown in cancer stem cells (CSCs) played a crucial role in tumorigenesis, tumor resistance, tumor recurrence, and tumor metastasis. Therefore, elucidation of CSCs biology can improve diagnosis, enable targeted treatment, and guide the follow up of GI cancer patients. In order to achieve chemoquiescence, seizing cancer through complete ablation of CSCs, CSCs are rational targets for the design of interventions that will enhance responsiveness to traditional therapeutic strategies and contribute in the prevention of local recurrence as well as metastasis. However, current cancer treatment strategies fail to either detect or differentiate the CSCs from their non-tumorigenic progenies mostly due to the absence of specific biomarkers and potent agents to kill CSCs. Recent advances in knowledge of CSCs enable to produce several candidates to ablate CSCs in gastrointestinal (GI) cancers, especially cancers originated from inflammation-driven mutagenesis such as Barrett's esophagus (BE), Helicobacter pylori-associated gastric cancer, and colitis-associated cancer (CAC). Our research teams elucidated through revisiting old drugs that proton pump inhibitor (PPI) and potassium competitive acid blocker (p-CAB) beyond authentic acid suppression, chloroquine for autophage inhibition, sonic hedgehog (SHH) inhibitors, and Wnt/β-catenin/NOTCH inhibitor can ablate CSCs specifically and efficiently. Furthermore, nanoformulations of these molecules could provide an additional advantage for more selective targeting of the pathways existing in CSCs just like current molecular targeted therapeutics and sustained action, while normal stem cells intact. In this review article, the novel approach specifically to ablate CSCs existing in GI cancers will be introduced with the introduction of explored mode of action.