The Combination of Three Natural Compounds Effectively Prevented Lung Carcinogenesis by Optimal Wound Healing
November
The Combination of Three Natural Compounds Effectively Prevented Lung Carcinogenesis by Optimal Wound Healing
Linxin Liu 0 1
Hong Li 0 1
Zhenzhen Guo 0 1
Xiaofang Ma 0 1
Ning Cao 0 1
Yaqiu Zheng 0 1
Shengnan Geng 0 1
Yongjian Duan 0 1
Guang Han 0 1
Gangjun Du 0 1
0 1 Institute of Pharmacy, Pharmacy College of Henan University , Jinming District, Kaifeng, Henan Province 475004, China , 2 Department of Oncology, The first hospital Affiliated to Henan University , Kaifeng, Henan Province 475001 , China
1 Editor: Hua Zhou, Macau University of Science and Technology , MACAO
The tumor stroma has been described as “normal wound healing gone awry”. We explored whether the restoration of a wound healing-like microenvironment may facilitate tumor healing. Firstly, we screened three natural compounds (shikonin, notoginsenoside R1 and aconitine) from wound healing agents and evaluated the efficacies of wound healing microenvironment for limiting single agent-elicited carcinogenesis and two-stage carcinogenesis. The results showed that three compounds used alone could promote wound healing but had unfavorable efficacy to exert wound healing, and that the combination of three compounds made up treatment disadvantage of a single compound in wound healing and led to optimal wound healing. Although individual treatment with these agents may prevent cancer, they were not effective for the treatment of established tumors. However, combination treatment with these three compounds almost completely prevented urethane-induced lung carcinogenesis and reduced tumor burden. Different from previous studies, we found that urethane-induced lung carcinogenesis was associated with lung injury independent of pulmonary inflammation. LPS-induced pulmonary inflammation did not increase lung carcinogenesis, whereas decreased pulmonary inflammation by macrophage depletion promoted lung carcinogenesis. In addition, urethane damaged wound healing in skin excision wound model, reversed lung carcinogenic efficacy by the combination of three compounds was consistent with skin wound healing. Further, the combination of these three agents reduced the number of lung cancer stem cells (CSCs) by inducing cell differentiation, restoration of gap junction intercellular communication (GJIC) and blockade of the epithelial-tomesenchymal transition (EMT). Our results suggest that restoration of a wound healing microenvironment represents an effective strategy for cancer prevention.
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OPEN ACCESS
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Competing Interests: The authors have declared
that no competing interests exist.
Introduction
Although conventional anticancer therapies, which consist of surgical resection, radiotherapy
and chemotherapy, are effective in the management of many patients, they are ineffective for
approximately half of cancer patients [
1
]. Resistance to conventional anticancer therapies in
patients with advanced solid tumors has prompted the need for alternative cancer therapies
[
2
]. Accumulating evidence suggests that cells and factors of the tumor microenvironment
decisively contribute to not only the survival of primary neoplastic cells but also to the
subsequent key events of neoplastic disease progression, including tumor growth, invasion, and
metastasis [
3
]. Epidemiologically, chronic wound states are well-known risk factors for cancer
development [
4
]. Furthermore, aberrant wound healing with chronic inflammation can
reportedly promote malignant transformation [
5
]. These phenomena have further solidified the view
of cancer as “a wound that does not heal” [
6
]. Studies of the role of aberrant wound healing in
cancer pathologies will be important for the discovery of novel therapeutics that can promote
wound healing or abrogate carcinogenesis in the tumor microenvironment.
Clearing a wound bed of nonviable tissue is increasingly acknowledged as an important step
that may facilitate the healing process for a variety of wound types, particularly chronic wounds
[
7
]. Necrotic tissue in the wound bed will significantly delay and in some cases prevent healing,
as it may serve as a reservoir for bacterial growth, contain elevated levels of inflammatory
mediators that promote chronic inflammation at the wound site, and impair the cellular
migration that is necessary for wound repair [
8
]. However, the factors that dictate the delicate
balance between normal wound repair and aberrant wound healing are yet to be fully elucidated.
We hypothesized that appropriate regeneration, sufficient oxygen supply and waste
elimination may regulate aberrant wound healing and facilitate tumor elimination. To stringently test
this wound healing hypothesis, we screened three natural compounds (shikonin,
notoginsenoside R1 and aconitine) from wound healing agents and created an optimal wound healing
microenvironment. Specifically, we observed the effects (...truncated)