Academic crowdfunding platform "academist"
JP | EN

Contributing to cancer treatment by tumor-selective toxicity

Profile
Yoshihiro Suzuki-Karasaki
Plasma ChemiBio Laboratory / Representative Director
Pledged: 1,142,200 JPY
Target Amount: 700,000 JPY
Funded
163 %
Supporters
23
Days left
Closed
Support this project

Reached the funding target!

Profile

Comment from academist staff

Img 6854

miho otsuka

Biological impacts of reactive oxygen species (ROS)

Without dioxygen (so-called oxygen, O2) in the air, most living things including us could not live while the molecule by itself is highly toxic for them, and one call this nature as oxygen toxicity. We can survive owing to the occurrence of an adequate concentration (20%) of oxygen in the air. Imagine that the air was solely composed of oxygen (it means the oxygen concentration in the air was 100%!), we would die at once by severe oxidative damages of virtually all organs especially lung and brain. The toxicity is a result of the excessive activity of oxygen, resulting from its unique biradical structure (•O=O• because the ground state of oxygen is a triplet (3O2).

Radicals represent chemical species with an unpaired electron. Electrons in molecules can stably exist a priori by making pairs. Accordingly, radicals are chemically very unstable and tend to make an electron pair by robbing electrons from another molecule. So, the biradical oxygen molecule is also chemically active to react with electrons, thereby producing more active, unstable reactive oxygen species (ROS). They include the singlet oxygen (1O2), the exciting state of oxygen, superoxide anion radical shortly superoxide (O2•-) and hydrogen peroxide (H2O2), which are made by one and two electron addition, respectively to biradical oxygen, and more active hydroxy radical (•OH), which is formed by means of the reduction of H2O2 by metal ions such as ferrous and cuprous ions (Fe2+/Cu+). Excess ROS can react with various macromolecules in cells including nucleic acids, proteins, and lipids nonspecifically, thereby damaging them. So, it is generally believed ROS are profoundly harmful to health possibly by causing a variety of chronic diseases such as arteriosclerosis, diabetes, cancer, and aging. However, an increasing body of evidence suggests that an appropriate level of ROS are critical and even essential for maintaining homeostasis by regulating a variety of biological processes including gene expression. Indeed, ROS have a dual action on cell growth and survival depending on the conditions such as cell type and dose, and exposure time. For example, H2O2 can lead to cell activation and increased proliferation as well as reduced cell growth and cell death depending on the conditions. The primary site of ROS production in the cell is mitochondria where O2 is gradually reduced to water in association with the production of energy (ATP) by oxidative phosphorylation in the electron transport complex (ETC). This energy-generating process necessarily produces ROS as a byproduct. Accordingly, the mitochondria are the site where energy and ROS are continuously produced together.

Because ROS act as a “Ninja in Japan” by successively transforming their shapes, it is rather difficult to catch them in the real-time and determine their chemical identity responsible for a given biological response. So, for most researchers, ROS were unfamiliar research theme at that time. However, my policy of research is that avoiding big field and studying based on unique aspects and hypotheses as possible. This policy led me to basic research on the biological impacts of ROS since 1993. In 2008, the achievement of this basic research opened a way to contribute to cancer treatment in the form of “tumor-selective toxicity.”

ROS is a critical factor in tumor-selective toxicity

The term “tumor-selective toxicity” stands for the toxicity selective for neoplasms. I encountered the term of “Magic Bullets” for the first time in 2008 at EHRLICH II, World Congress on Magic Bullets, an International Meeting held in Nürnberg, Germany, to where I was invited to give a talk by German Pharmaceutical Society. This meeting was held to celebrate the 100th Anniversary of Novel Prize Awarded to Paul Ehrich. In 1907, he proposed the concept of chemotherapy. In this idea, he stated “Magic Bullets,” a virtual drug being effective toward microorganisms while being harmless toward the human body. In the case of anticancer drugs, they should be highly toxic toward neoplasms while displaying minimal toxicity toward normal tissues. However, anticancer drugs used in conventional cancer “chemotherapy” have poor tumor-selectivity leading to serious side effects from that time. Strictly speaking, no ideal cancer chemotherapy could be accomplished unless we can hand Magic Bullets against cancers. So, I heartily wished to find the principle of tumor-selectivity and open a way to generate such weapons.

Eventually, we discovered that mitochondrial O2•- accumulation triggers mitochondrial and endoplasmic reticulum dysfunctions, thereby leading to non-apoptotic cell death. Our data also strongly suggested that the source of the O2•- generation may be the ETC in the mitochondria. H2O2 is a relatively stable oxidant species in the absence of destroying enzymes such as glutathione peroxidase, peroxidase, and catalase, and so that can be added exogenously. (The commercially available disinfectant Oxydol usually contains approx. 3% hydrogen peroxide solution). In 2013, to our surprise, as little as 0.00034% (100 μM) of H2O2 could kill TRAIL-resistant malignant tumor cells such as lung cancer, melanoma, and osteosarcoma cells. More surprisingly, under the conditions the oxidant had minimal cytotoxicity toward normal cells such as dermal and lung fibroblasts and melanocytes. In conclusion, ROS are emerging as a critical factor in the principle of tumor-selective toxicity through non-apoptotic cell death induction.

B2

Mitochondrial network aberration and non-apoptotic cell death

In 2014~2016 Our mechanistic studies revealed that mitochondrial network aberration contributed to tumor-selective toxicity of H2O2. Mitochondria are highly dynamic organelles with a reticular network organization. Mitochondrial morphology is known to be critical for cell function and apoptosis.

The mitochondrial network depends on the delicate balance between two opposing types of machinery responsible for fission and fusion of the mitochondrial membranes. As a result, the mitochondrion exists separately (fission) or exist an organized form (fusion). An imbalance of this dynamics results in a malfunction in energy production, leading to non-apoptotic cell death. We found that H2O2 led to altered status of genes controlling the balance through oxidative stress, thereby causing mitochondrial network disruption. We also discovered that mitochondrial O2•- accumulation facilitated increased plasma membrane depolarization, a promoter of mitochondrial network aberration and that the oxidative and membrane potential dysregulation occurred in tumor cells, but not in normal cells.

A chain of our findings leads to a beautiful hypothesis that tumor cells are more prone than normal cells to mitochondrial oxidative stress, thereby being more vulnerable to mitochondrial network aberration and non-apoptotic cell death induction. It is the decisive moment that the past achievements of the basic research on ROS and mitochondria opened the way to cancer treatment in the viewpoint of tumor-selective toxicity.

How about using plasma as a tool for fighting cancers?

Just when we accumulated the findings regarding the role of ROS in tumor-selective toxicity, I got an e-mail from a researcher working for CSIRO (Commonwealth Scientific and Industrial Research Organization) in Australia. The mail described that non-thermal (cold) atmospheric plasma (CAP) has tumor-selective cytotoxicity by poorly understood mechanism unless ROS mediate it. It was an exciting invitation to join the research group as an expert of ROS. At a glance, I felt that CAP might utilize mechanisms similar to TRAIL and H2O2 so that the past achievements could be available. Unfortunately, depending on various reasons I could not accept this challenging invitation at that time, but in the later, I encountered another chance to treat CAP.

Plasma stands for the fourth state of materials that follows solid, liquid, and gas, in which the atoms in a gas are separated into the atomic nuclei and electrons by massive energy, and thereby moving together. Recent technical innovation of the plasma field enabled to make a great plasma under cold (nearly at room temperature) and atmospheric pressure conditions and called as CAP. Because CAP readily and effectively modulates physical properties, it has been widely applied in the field of engineering.

Since CAP has been shown to have tumor-selective cytotoxicity about ten years ago, it has emerged as a promising tool for fighting cancers. However, there were several problems to be solved to serve a practical use. The critical one is that the primary application of CAP may be limited to surface cancerous tissues because of a little outreach except in situ irradiation during laparoscopic or abdominal surgery. Another one is that the precise mechanisms of the action remained largely unclear except the involvement of ROS.

Basic research for practical realization of cancer treatment

To expand CAP application to internal cancers, we used plasma-irradiated liquid (PLAIL) in place of direct CAP irradiation because one can readily administer the solutions systemically or locally by intravenous drip or endoscope. In 2016~2018, we discovered that PLAIL contained H2O2, which in turn evoke mitochondrial O2•- accumulation, leading to mitochondrial network aberration and non-apoptotic cell death. As observed with H2O2, tumor cells were much more vulnerable than normal cells to the cell death induction, these pro-death events including mitochondrial ROS accumulation induced by PLAIL. The emerging view is that altered metabolism and genetic instability under the control of oncogenic transformation cause increased ROS generation and decreased antioxidant system in cancer cells. As a result, they may burden excess oxidative stress over normal cells. Together, it is likely that the susceptibility to mitochondrial ROS accumulation leads to the tumor-selective toxicity of PLAIL.

As PLAIL also contained another unknown component that strengthens the anticancer activity, it exerts greater anticancer effect and mitochondrial modulating ability compared with H2O2. Also, our recent data suggest that depending on the plasma species and target solutions, PLAIL can kill cancer cells by different cell death modalities including autophagy and, necroptosis. Many of conventional anticancer drugs target apoptosis while cancers are characteristics to possess various types of machinery preventing apoptosis. By contrast, PLAIL can attack cancer cells by targeting different cell death modalities thereby exerting a potent anticancer activity.

B5

Why we need your support

PLAIL displays a drastic anticancer effect toward various cancer cell types in vitro. Our collaborators working for another university reproduced the results in their laboratory, too and performed in vivo experiments using cancer-bearing animal models. In the experiments, PLAIL exhibited a dramatic reduction in tumor growth and minimal weight loss and side effects. As a result, PLAIL has merged as a promising candidate for “Magic Bullets” fighting against cancers. After my presentation of these facts at the meeting, clinicians encouraged the PLAIL project and strongly demanded the practical realization of PLAIL in clinical use. I felt a strong expectation for cancer treatment by PLAIL. Also, I was sure that it is an excellent chance to return the past achievements of the basic research to the world. So, with my retirement of the university as a turning point, I earnestly aimed to put PLAIL into practical use by establishing a private institute of a research laboratory.

The PLAIL project has two different goals. The first one is the practical realization of PLAIL which needs experiments in patients regarding the efficacy and side effects. For this purpose, we are currently collaborating with several clinicians to perform pre-clinical studies. The trouble to be resolved from now on is large-scale production of PLAIL. The present method only can serve a laboratory-scale of PLAIL which is insufficient for application to patients. So, we are also currently working on the development of auto PLAIL producing machine in cooperation with a precision apparatus company. Another goal is that of basic research. We aim to know the principle of tumor-selective toxicity by using PLAIL as a model. To this aim, we are going to characterize the cell death modalities targeted by PLAIL and elucidate the precise mechanisms of mitochondrial network aberration.

We have two reasons for challenging the Crowd Funding in Academist. One reason is, of course, the acquisition of a research fund, another reason is the distribution of the final goal of the PLAIL project — namely, the practical realization of cancer treatment by PLAIL without side effect. The support grant will be help for the purchase of research equipments. It sounds great if this project inspires your sympathy and support. The challenging project needs your support now!

Support
Profile

I am Dr. Yoshihiro Suzuki-Karasaki. I am a scientist who has already retired from the teaching profession at the university but is still a researcher with a young heart. Throughout my academic carrier, I have been engaging the basic research on the mechanisms of the control of cell death and survival with a particular interest in the role of ROS and mitochondria. In this process I have discovered the drastic and highly tumor-selective toxic effect of PLAIL. With my retirement of the university as a turning point, I have established a private research institute for chemical biology. Currently, the primary research project in our laboratory is the PLAIL project— that aims to understand the principle of the tumor-selective toxicity of PLAIL and to put PLAIL into practical use cooperatively with scientists in inside and outside of Japan. Unlike the days throughout my acting career, I am really enjoying every day with a stress-free study and speculation in the forest. (All bothers me is the invasion of various types of insects to my office because of too much greenery).

Profile

Yoshihiro Suzuki-Karasaki

Project timeline

Date Plans
February 2019 The Crowd Funding Challenge start
May 2019 Introduce the experimental apparatus
October 2019 Presentation at 24th World Congress on Advances in Oncology(Sparta, Greece)
December 2019 Submit the paper

Pledge Rewards

1,000 JPY (Tax not included)
Featured: Send Research Report “PCBL Letter” to you (PDF)
Send Research Report “PCBL Letter” to you (PDF)
1000

The supporter can know the progress in the PLAIL project, current presentations at the meetings, and the content of the paper by e-mail.

6 supporters are supporting with this reward. (Non quantity limit)

5,000 JPY (Tax not included)
Featured: Display your name on the website
Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)
5000

Your name will appear at PCBL official account home page as a supporter.

5 supporters are supporting with this reward. (Non quantity limit)

10,000 JPY (Tax not included)
Featured: Invite to Science Café
Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)
10000

Welcome to our Science café, which will be held at our institute twice a year (May and December) in 2019 (Detail information will be informed by e-mail). At the meeting, we have a plan to have a brief talk about the project, cancers, and cancer research. We can also present the current status and progress in the project. Specifically, all attendance can frankly exchange view with specially made Royal Milk Tea (PCBL-special) in their hand. Sorry, we cannot offer any transport expenses and accommodation fees. We are looking forward to your attendance! *We will send the detailed information to supporters not attending the meeting.

6 supporters are supporting with this reward. (Non quantity limit)

30,000 JPY (Tax not included)
Featured: Display your name on the acknowledgments of a presentation at a meeting
Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)
30000

Display your name on the acknowledgments of all presentations about the project at the coming 24th World Congress on Advances in Oncology, which will be held in Sparta, Greece 10~12 October in 2019. Also, we will gift the content of the paper (electronic version).

0 supporters are supporting with this reward. (Non quantity limit)

50,000 JPY (Tax not included)
Featured: Display your name on the acknowledgments of a paper in an international journal
Display your name on the acknowledgments of a paper in an international journal / Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)
50000

Display your name on the acknowledgments of all papers reporting the achievements of the project.

1 supporters are supporting with this reward. (Non quantity limit)

100,000 JPY (Tax not included)
Featured: Gift a letter of appreciation and invite you to visit our institute
Invite you to visit our institute / Display your name on the acknowledgments of a paper in an international journal / Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)
100000

Invite you to visit our institute. You can look at cultured cancer cells and the morphology of mitochondria by excellent microscopy and the generation of plasma jet in the real-time there. The day of the visit will be determined by discussion.

0 supporters are supporting with this reward. (Non quantity limit)

200,000 JPY (Tax not included)
Featured: Lecture with a business trip
Lecture with a business trip / Invite you to visit our institute / Display your name on the acknowledgments of a paper in an international journal / Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)

We can visit anywhere to give a talk about anything regarding plasma, PLAIL, and cancer on your demand. We need at least five attendance at the meeting. Sorry, we also need transport expenses and accommodation fees in the case of a business trip abroad.

5 supporters are supporting with this reward. (Non quantity limit)

Supporters will be charged the funding amount only if the project reaches the funding goal (JPY 700,000) before 2019年04月23日 19時00分 (JST: GMT+9).
Payment options
Credit cards (VISA, Mastercard) are available
Available cards
Bank transfer

Please contact us if you'd like to pay by bank transfer.

Securities

SSL encryption communication is used in this Web site, and the informations filled out are safely transmitted.

1,000 JPY (tax excluded)

Send Research Report “PCBL Letter” to you (PDF)

1000

6 supporters back
(Non quantity limit)

5,000 JPY (tax excluded)

Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)

5000

5 supporters back
(Non quantity limit)

10,000 JPY (tax excluded)

Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)

10000

6 supporters back
(Non quantity limit)

30,000 JPY (tax excluded)

Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)

30000

0 supporters back
(Non quantity limit)

50,000 JPY (tax excluded)

Display your name on the acknowledgments of a paper in an international journal / Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)

50000

1 supporters back
(Non quantity limit)

100,000 JPY (tax excluded)

Invite you to visit our institute / Display your name on the acknowledgments of a paper in an international journal / Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)

100000

0 supporters back
(Non quantity limit)

200,000 JPY (tax excluded)

Lecture with a business trip / Invite you to visit our institute / Display your name on the acknowledgments of a paper in an international journal / Display your name on the acknowledgments of a presentation at a meeting / Invite to Science Café / Display your name on the website / Send Research Report “PCBL Letter” to you (PDF)

5 supporters back
(Non quantity limit)

Featured projects

Copyright © academist, Inc. All rights Reserved.