Abstract
Background: Next to breast cancer, advanced stage metastatic colon cancer represents a major cause for mortality in women. Germline or somatic mutations in tumor suppressor genes or in DNA mismatch repair genes represent risk factors for genetic predisposition of colon cancer that are also detectable in sporadic colon cancer. Conventional chemotherapy for colon cancer includes combination of 5-fluoro-uracil with oxaliplatin and irinotecan or targeted therapy with non-steroid anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors. Major limitations of these therapeutic interventions are associated with systemic toxicity, acquired tumor resistance and the emergence of drug resistant stem cells that favor initiation, progression and metastasis of therapy-resistant disease. These limitations emphasize an unmet need to identify tumor stem cell selective testable alternatives. Drug-resistant stem cell models facilitate the identification of new testable alternatives from natural phytochemicals and herbal formulations. The goal of this review is to provide an overview relevant to the current status of conventional/targeted therapy, the role of cancer stem cells and the status of testable alternatives for therapy-resistant colon cancer. Experimental models: Hyper-proliferative and tumorigenic cell lines from genetically predisposed colonic tissues of female mice represent experimental models. Chemotherapeutic agents select drug-resistant phenotypes that exhibit upregulated expressions of cellular and molecular stem cell markers. Mechanistically distinct natural phytochemicals effectively inhibit stem cell growth and downregulate the expressions of stem cell markers. Conclusions: The present review discusses the status of colon cancer therapy and inherent limitations, cancer stem cell biology, potential lead compounds and their advantages over chemotherapy. The present experimental approaches will facilitate the identification of pharmacological and naturally-occurring agents as lead compounds for stem cell targeted therapy of colon cancer.
Highlights
The progression of breast and colon cancer to advanced stage metastatic disease represent major causes of mortality in women
Whereas it is well-established that estrogens represent a positive growth regulatory endocrine factor for breast cancer, the role of endocrine factors in colon cancer is less defined
Herbal formulations consisting of multiple Chinese nutritional herbs are widely used in traditional Chinese medicine for treatment of triple negative breast cancer (TNBC) and their growth inhibitory efficacy is predominantly via inhibition of Phospho-inositidyl-3 kinase (PI3K), protein kinase B (AKT), molecular target of rapamycin, mitogen activated protein kinase (MAPK) and Wnt/β-catenin pathways [36]
Summary
The progression of breast and colon cancer to advanced stage metastatic disease represent major causes of mortality in women. Targeted therapy for colon cancer uses non-steroidal antiinflammatory drugs that target cyclooxygenases (COX-1 and COX-2), selective inhibitors of (COX-2) and selective inhibitors of ornithine decarboxylase (ODC), a rate-limiting enzyme in the polyamine biosynthesis pathway The efficacy of these targeted therapeutic options has been documented in preclinical models. In the same model administration of selective COX-2 inhibitor celecoxib (CLX) either early or late during the carcinogenic process results in the inhibition of polyp or adenoma formation, respectively, suggesting preventive or therapeutic efficacy [11]. These two agents have documented clinical efficacy in patients with genetically predisposed and sporadic colon cancer [12,13]. This review discusses experimental evidence relevant to: (i) Development and characterization of cellular models for genetically predisposed colon cancer; (ii) Growth inhibitory efficacy of naturally-occurring and pharmacologic agents; (iii) Development and characterization of drug-resistant stem cell models; and (iv) Leads for efficacy of naturally-occurring agents on cancer stem cells
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