Related Experiment Video
Updated: May 31, 2025
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Prostate cancer-selective anticancer action of an oxindole derivative via HO-1-mediated disruption of metabolic
Kalpana Ghimire1, Bhuwan Prasad Awasthi1, Kiran Yadav1
1College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
Abstract:
Prostate cancer, the second leading cause of cancer-related mortality in men, exhibits distinct metabolic reprogramming involving zinc and citrate metabolism. This study investigated whether targeting this unique metabolic profile could offer an effective therapeutic approach. A series of novel oxindole derivatives were synthesized and evaluated for their inhibitory effects on transcription factors (TFs) and antiproliferative activity across various cancer cell lines. Among these, compound 3D showed the strongest inhibition of master TFs (HIF-1α, c-Myc, and SP-1) and demonstrated selective antiproliferative activity in prostate cancer cells. In PC-3 and LNCaP cells, compound 3D suppressed aerobic glycolysis by downregulating lactate-modulating genes (LDHA, MCT1/4, and CAIX) and the zinc influx transporter (ZIP1), without affecting the zinc efflux transporter (ZnT4). Notably, 3D selectively increased heme oxygenase-1 (HO-1) levels in prostate cancer cells, as shown by the proteome profiler oncogene array assay and confirmed by Western blotting. This response was reversed by ZnCl2 treatment. The decreases in LDHA, mitochondrial mass (measured by FACS), and cell proliferation induced by compound 3D were blocked by HO-1-IN-1, an HO-1 inhibitor, and ZnCl2. Furthermore, 3D induced a more pronounced reduction in the oxygen consumption rate (OCR) than in the extracellular acidification rate (EACR), indicating a strong effect on oxidative metabolism. 3D exhibited dose-dependent antitumour efficacy in vivo comparable to that of docetaxel. These findings reveal that the oxindole derivative 3D substantially lowers intracellular zinc levels, yielding potent antitumour effects in prostate cancer through HO-1 upregulation, which impairs mitochondrial function more significantly than aerobic glycolysis.
Insights
A novel oxindole derivative, compound 3D, effectively targets prostate cancer by lowering intracellular zinc levels. This leads to potent antitumor effects via heme oxygenase-1 upregulation, impairing mitochondrial function and inhibiting cancer cell growth.
Area of Science:
- Oncology
- Metabolic Pathways
- Medicinal Chemistry
Background:
- Prostate cancer is a leading cause of male cancer mortality, characterized by unique metabolic alterations in zinc and citrate metabolism.
- Targeting these specific metabolic vulnerabilities presents a potential therapeutic strategy.
Purpose of the Study:
- To synthesize and evaluate novel oxindole derivatives for their ability to inhibit key transcription factors and inhibit proliferation in cancer cells.
- To investigate the therapeutic potential of compound 3D in prostate cancer by elucidating its mechanism of action.
Main Methods:
- Synthesis and antiproliferative screening of oxindole derivatives against various cancer cell lines.
- Assessment of inhibitory effects on transcription factors (HIF-1α, c-Myc, SP-1).
- Analysis of gene expression (LDHA, MCT1/4, CAIX, ZIP1, ZnT4), protein levels (HO-1), mitochondrial mass (FACS), oxygen consumption rate (OCR), and extracellular acidification rate (EACR).
- In vivo efficacy studies in mouse models.
Main Results:
- Compound 3D demonstrated potent inhibition of master transcription factors and selective antiproliferative activity in prostate cancer cells.
- 3D suppressed aerobic glycolysis by downregulating key lactate-modulating genes and the zinc influx transporter ZIP1.
- Selective upregulation of heme oxygenase-1 (HO-1) in prostate cancer cells was observed, which was reversed by zinc chloride (ZnCl2).
- 3D significantly impacted oxidative metabolism, showing a greater reduction in OCR than EACR.
- In vivo studies showed dose-dependent antitumor efficacy comparable to docetaxel.
Conclusions:
- The oxindole derivative 3D exhibits significant antitumor effects in prostate cancer by reducing intracellular zinc levels.
- HO-1 upregulation plays a crucial role in 3D's mechanism, leading to impaired mitochondrial function and reduced cell proliferation.
- Compound 3D represents a promising therapeutic candidate for prostate cancer, targeting its unique metabolic profile.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34Inhibition of Cdk Activity
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:23Abnormal Proliferation