CXC Chemokine Ligand 8 Is the Modulator of Cadmium-Induced Prostate Carcinogenesis
Abstract
Cadmium (Cd) is a toxic heavy metal found as a contaminant or a component of many modern-day items. It is present in cigarettes, Ni-Cad batteries, paint, and imitation jewelry. Cd is a highly reactive chemical that accumulates in the body and potentially causes long-term damage, including lethal cancers. It is a silent killer. Many scientific studies have reported a high level of cadmium in human tissues, including the lung, liver, kidney, testis, and prostate. Once entered into the tissues, it stays for decades, causing damage. Since prostate cancer (PCa) ranks second in cancer incidence and deaths in industrialized countries such as the United States and Western Europe, from a health standpoint, it is critical to study how Cd exposure causes malignant prostate cancer and how to prevent it. Many studies have reported significantly higher levels of Cd in advanced PCa than in low-grade tumors or normal prostate tissues. Studies have shown that even low-level exposure over nine weeks can turn normal prostate epithelial cells into cancer cells that form tumors when injected into immune-tolerant mice. However, what culprit (a mechanism) that drives the development of PCa following Cd exposure and how to target it is poorly understood. The primary goal of this project is to understand how Cd exposure leads to the development of malignant PCa and how to prevent it. More importantly, can we prevent the Cd toxicity leading to the development of PCa, and toxicities and malignancies in other organs, by using non-toxic oral agents that target a likely culprit that drives Cd-induced toxicities and malignancies? Cd is known to be a weak mutagen but a strong superoxide generator and depletes the essential element Zinc in the tissues in which it accumulates. Therefore, it is hypothesized that Cd promotes inflammation and cancer progression from non-invasive to invasive cancers. In preliminary studies, we found one predominant proinflammatory protein called Interleukin-8 (IL-8), secreted by prostate epithelial cells when exposed to Cd in as early as one week. But their malignant transformation occurs following nine weeks of Cd-exposure. The malignant transformation is characterized by increased growth, invasive activity, and the ability to induce new blood vessel growth (angiogenesis). Blocking the IL-8 signaling inhibited Cd’s malignant effects. We have reported that IL-8 increases in invasive and metastatic PCa patients and promotes prostate tumor growth, metastasis, angiogenesis, and resistance to treatment. Other works show that IL-8 makes neutrophils migrate to the injury site and stimulates growth factor secretion, which helps angiogenesis and metastasis. An inhibitor of IL-8 functions, Navarixin (NVX), has anti-inflammatory effects. NVX is undergoing clinical trials to treat advanced cancers. NVX may help curb Cd’s activity on malignant transformation by inhibiting IL-8 function. Our team has developed another small molecule inhibitor of inflammation and cancer growth called CMC2. CMC2 orally inhibited aggressive breast cancer growth in mice without toxicity. Therefore, CMC2 could be another preventive agent to curb toxicities and malignancies inflected by Cd exposure. We have proposed to test the role of IL-8 in the progression to lethal cancer using pre-clinical cell culture and animal models in which we will modulate intracellular production of IL-8 (Aims 1, 2) with genetic manipulation. This project aims to test the role of IL-8 in Cd-induced malignancy, prevention by oral administration (gastro-intestinal lavage or gavage) of CMC2 or NVX, and prevention of long-term toxicity of Cd using a mouse model of Cd-induced tissue damage. We will test the efficacy of NVX and CMC2 to inhibit tumor formation and tumor growth created by Cd-transformed prostate epithelial cells injected under the skin of immune-tolerant mice. We anticipate no-tumor or tiny, non-invasive tumors in mice treated with NVX or CMC2.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310761
Entities
People
- Bal Lokeshwar
Organizations
- Augusta University
- United States Army