Antimetastatic Mechanisms of Bisdioxopiperazine Compound Study, A
Gateway to Success
Da-Yong Lu1,2*, Jian Ding1, Rui-Ting Chen1, Bin Xu1, Nagendra Sastry Yarla3 and Ting-Ren Lu2
1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China
2Shanghai University, Shanghai, PR China
3GITAM University, AP, India
- *Corresponding Author:
- Da-Yong Lu
Shanghai Institute of Materia Medica
Chinese Academy of Sciences, Shanghai 201203
E-mail: [email protected]
Received date: August 15, 2017; Accepted date: August 20, 2017; Published date: August 30, 2017
Citation: Lu DY, Ding J, Chen RT, Xu H, Yarla NS, et al. (2017) Antimetastatic Mechanisms of Bisdioxopiperazine Compound Study, A Gateway
to Success. J Cell Mol Pharmacol 1:e101.
Copyright: © 2017 Lu DY, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Journal of Cellular and Molecular Pharmacology
Neoplasm metastasis is the causality of 90% cancer patient’s mortality. Bisdioxopiperazine compounds (Biz
compounds) are a series of synthetic agents that are firstly discovered to exhibit antimetastatic efficacy to animal
tumor models. In order to completely overcome neoplasm metastasis in clinics, antimetastatic therapeutic study for
Biz compounds is of great clinical significance. This editorial highlights these researches from new perspective.
Bisdioxopiperazine compounds; Probimane; Razoxane;
MST-16; Antimetastatic drugs; Neoplasm metastasis; Drug
combinations, Drug development
Cancer is one of the deadliest diseases that cause the 7-10 millions
deaths annually worldwide [1-2]. Neoplasm metastasis is prime factor
for patient’s deaths (approximately 90% of cancer mortality).
Therapeutic benefits in late-staged or aged cancer patients are
especially poor and useless [3-4]. Clinical anticancer drug therapies
currently in use are mainly focusing on primary tumor growth rather
than specifically targeting pathologic courses of metastases. It
nevertheless needs changing mindset into other types of drug targets
and personalized cancer therapy in clinics [4-7]. One of them is the
revisiting of Biz compound study [8-9].
Inventions of Biz Compounds
Biz compounds are a series of synthetic agents that are firstly
discovered to exhibit antimetastatic efficacy to animal tumor model. In
order to completely overcome neoplasm metastasis in clinics,
antimetastatic therapeutic study for Biz compounds is of great clinical
significance. Since Biz compounds are unique agents in their pharmacological mechanisms of action of metastases inhibition and
are conservative anticancer and antimetastatic activities between Biz
compounds, further medicinal chemistry or pharmacological studies
seems indispensable [8-10]. The structural formulae of the major Biz
compounds are represented in Figure 1.
Figure 1: Structural formulae of major bisdioxopiperazine
Biz compounds are the earliest anticancer agents found to especially
inhibit spontaneous neoplasm metastases [12-14]. Due to these earliest
discoveries on neoplasm metastasis inhibition, Biz compounds are
widely noticed for cancer metastasis treatment study. So far, a lot of
new anticancer activity and mechanisms of Biz compounds have been
found [15-31]. Accordingly, it is proposed that anticancer and antimetastatic mechanisms of Biz compounds can be a medical gateway for completely understanding into neoplasm metastasis
pathogenesis and their therapeutics in clinics.
The major drawback of Biz compounds is low antimetastatic efficacy
in clinical trials. Most of past discoveries are come from experimental
data. In addition, the debate of high risk of carcinogenesis from Biz
compound treatments is difficult to conclude [32-33]. Since there is no
definite pathway of anti-metastatic drug developments, we thus
suggest that Biz compounds should be carefully studies for both
experimental investigations and clinical applications in cancer
treatments. Today, we are in front of widely therapeutic failure in
cancer metastasis treatments [4-5]. To change this scenario, new
generation of pharmacologic/medical researches for Biz compounds,
such as personalized cancer treatments  are urgently needed.
In summary, we address and highlight the different inhibitions
against metastases in vivo and molecular mechanisms in vitro of Biz compounds, especially relating to the inhibitions of tumor metastasis
including pathways of angiogenesis, topoisomerase II, calmodulin,
sialic acid, fibrinogen, cell-movements and so on [12-31]. These kinds
of researches might be an avenue for the successes of neoplasm
- Siegel RL, Miller KD, Jemal A(2017) Cancer stastistics. CA-Cancer J Clin67:7-30.
- Ali I, Enein AY.H, Imran, Rahis-ud-din,Saleem K, et al. (2011) Social aspects of cancer genesis. Cancer Ther8:6-14.
- Varmus H(2006) The new era in cancer research. Science312:1162-1165.
- Lu DY, Lu TR, Wu HY (2013)Cancer metastases treatments. Curr Drug ther8:24-29.
- Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell147:275-292.
- Lu DY, Lu TR, Zhu H, Ding J,Xu B, et al.(2017)Anticancer drug development, getting out from bottleneck. Med Chem7: 739-744
- Lu DY, Lu TR, Chen EH, Nagendra SY, Bin XU,et al.(2017) Anticancer drug development, system updating and global participations. Curr Drug ther12:37-45.
- Lu DY, Lu TR(2010) Anticancer activities and mechanisms of bisdioxopiperazine compounds probimane and MST-16.Anticancer Agents Med Chem10:78-91.
- Lu DY, Lu TR (2010) Antimetastatic activities and mechanisms of bisdioxopiperazine compounds. Anticancer Agents Med Chem10:564-570.
- Ji RY (1988)Probimane. Drugs. Fut13:418-419
- Herman EH, Witiak DT, Hellmann K,Waravdekar VS, Properties of ICRF-159 and related Bis(dioxopiperazine) compounds. AdvPharmacolChemother. Garattini S, Goldin A, Hawking F, Kopin IJ (Edsn) Academy Press,New York.
- Hellmann K, Burrage K (1969) Control of malignant metastases by ICRF-159. Nature 224:273-275.
- James SE, Salsbury AJ(1974) Effect of (±)-1,2-bis(3,5-dioxopiperazin-1-yl) propane nontumor blood vessels and its relationship to the antimetastatic effect in the Lewis lung carcinoma. Cancer Res 34:839-842
- Lu DY, Xu B, Ding J(2004) Anti-tumor effects of two bisdioxopiperazines against two experimental lung cancer models in vivo. BMC Pharmacol4:32.
- Okamoto T, Nishimura Y, Yamada S, Itoh T, Mori A,et al.(2000) Long-term administration of oral low-dose topoisomerase II inhibitors, MST-16 and VP- 16, for refractory or relapsed non-Hodgkin’s lymphoma. Acta. Haematol104:128-130.
- Bakowski MT ICRF 159, (+/-) 1, 2-di (3, 5-dioxopiperazin-1-yl) propane NSC-129, 943; razoxane. Cancer Treat Rev 3: 95-107.
- O’connell MJ (1976) Randomized clinical trial comparing two dose regimens of ICRF-159 in refractory malignant lymphomas. Cancer Treat Rep 64:1355-1358
- Lu DY, Wu FG, Shen ZM,Lu RT,Wu HY, et al. (2010) Different spontaneous pulmonary metastasis inhibitions against Lewis lung carcinoma in mice by Bisdioxopiperazine compounds of different treatment schedules. Sci Pharm78:13-20.
- Lu DY, Chen RT, Lu TR, Wu HY, Qu RX,et al. (2010) The absorption, distribution and excretion of 14C-probimane in mice bearing Lewis lung carcinoma. Sci Pharm 78:445-450.
- Lu DY, Huang M, Xu CH, Yang WY, Hu CX, et al. (2005) Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines, BMC Pharmacology 5: 11.
- Lu DY, Huang M, Xu CH, Zhu H , Xu B, et al. (2006) Medicinal chemistry of probimane and MST-16: comparison of anticancer effects between bisdioxopiperazines. Med Chem 2: 369-375.
- Lu DY, Chen EH, Cao JY,Xu BJ, Ding J,et al. (2007)The antiproliferative effects of probimane and razoxane on tumor cells are concomitant with inhibition of hemolysis and calmodulin (CaM) action and a new CaM-ATPase acting model. Res J Biol Science 2:127-133.
- Lu DY, Lu TR, Ding J (2010) Cell manifestation of bisdioxopiperazines treatment of human tumor cells lines in culture. Anticancer Agents Med Chem, 10: 657-660.
- Hellmann K(2003) Dynamics of tumor angiogenesis: effect of razoxane- induced growth rate slowdown. ClinExp Metastasis20:95-102.
- Lu DY, Chi J, Lin LP, Huang M, Xu B, et al. (2004) Effect of anticancer drugs on the binding of 125I-fibrinogen to two leukemia cell lines in vitro. J. Int. Med. Res 32: 488-491.
- Lu DY, Xu J, Lu TR,Wu HY, Xu B,et al. (2013) Inhibitions of some antineoplastic drugs on serum sialic acid levels in mice bearing tumors. Sci Pharm 81:223-231.
- Lu DY, Liang G, Zhang MJ,Xu B(1994) Serum contents of sialic acids in mice bearing different tumors. Chin. Sci. Bull 39:1220-1223.
- Yang KZ (1990) Short-term results of malignant lymphoma treated with probimane. Chin J Cancer9:192-193.
- Lu DY, Chen EH, Cao JY (2001) Comparison between probimane and razoxane on inhibiting calmodulin activity of rabbit erythrocyte membrane. Chin J PharmacolToxicol15: 76-78.
- Lu DY, Chen EH, Cao JY (1991)The inhibition of probimane on lipoxidation of rabbit and human erythrocytes. J Shanghai University 7:301-304.
- Hellmann K, Rhomberg W. Radiotherapeutic enhancement by razoxane. Cancer Treat Rev 18, 225-240.
- Vuong MC, Hasegawa LS , Eastmond DA (2013) A comparative study of the cytotoxic and genotoxic effects of ICRF-154 and bimolane, two catalytic inhibitors of topoisomerase II. Mutat Res Genet Toxicol Environ Mutagen 750: 63-71.
- Barry EV, Vrooman LM, Dahlberg SE, Neuberg DS, Asselin BL, et al. (2008) Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J ClinOncol 26: 1106-1111.
- Lu DY (2014) Personalized cancer chemotherapy, an effective way for enhancing outcomes in clinics Woodhead Publishing, Elsevier, UK.