Aspirin, lysine, mifepristone and doxycycline combined can effectively and safely prevent and treat cancer metastasis: prevent seeds from gemmating on soil.

Liyuan Wan,Lee Jia,Fangwei Xie,Tao Li,Ting Zhang,Yu Gao,Xiaohuang Tu,Jingjing Xie,Yusheng Lu,Haiyan Dong,Jingwei Shao,Ji Ma,Yewei Zhu,Jichuang Wang,Huo Xu,Bo Xu

doi:10.18632/oncotarget.6038

Abstract

Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α4-integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity.

Highlights

The increased number of cancer survivors is the cause for celebration [1], but this expanding population has highlighted the problem of cancer relapse and metastasis after surgical removal of the primary tumors [2]
The adhesion and invasion of circulating tumor cells (CTCs) to endothelial cells are considered as the important initial step of distant cancer metastasis
Since HAMPT was defined as a cancer metastasis chemopreventive combination that showed high adhesion inhibition ratio (AIR) and inhibited the cell hetero-adhesion, we explored if HAMPT could affect the expression of those cell adhesion molecules by using flow cytometry as we described previously [16,17]

Summary

Introduction

The increased number of cancer survivors is the cause for celebration [1], but this expanding population has highlighted the problem of cancer relapse and metastasis after surgical removal of the primary tumors [2]. The emergence of disseminated metastases remains the primary cause of mortality in cancer patients [3], which is the daily threat to the cancer survivors, among them 30-70% will eventually face the metastatic nightmares within 2-5 years after surgery. The root cause of cancer metastasis can be traced down to the presence of circulating tumor cells (CTCs) or tumor-specific DNA in the blood of cancer survivors [4]. Chemotherapeutics cannot be used in the asymptomatic cancer survivors [7]. The activated CTCs possess more heterogeneity and drug tolerance than the normal cells [12]

Methods

Results

Conclusion