Pharmacogenetics of Target Genes Across Doxorubicin Disposition Pathway: A Review

Abstract

Increased understanding of the molecular mechanisms of tumor heterogeneity combined with rapid advances in the field of pharmacogenetics and pharmacogenomics have fuelled studies on individualizing anticancer therapy. Doxorubicin (Adriamycin), is an anthracycline glycoside antibiotic originally produced by Streptomyces peucetius var. caesius, and is widely used either as a single agent or in combination with other chemotherapeutic regimens for curative, adjuvant, and palliative treatment in cancer patients. The pharmacogenetics of doxorubicin has not been well characterized. The polygenic influence of functional candidate gene variants across doxorubicin biochemical pathway is hypothesized to contribute to its heterogeneity in disposition, influencing the efficacy of treatment and occurrence of adverse effects like cardiomyopathy in patients undergoing doxorubicin based adjuvant and neo-adjuvant chemotherapy. The pharmacogenetics of Asian population differs from that of other ethnic groups, particularly from Caucasian and African populations, and indicates an important role of ethnicity in determining predictive end points during chemotherapy and in individualizing treatment. This review comprehensively examines the pharmacogenetics of the regulatory nuclear receptor Pregnane-X Receptor (PXR), influx (SLC22A16) and efflux drug transporters (ABCB1, ABCG2, ABCC5, ABCB5 and RLIP76) and drug metabolizing enzymes (CBR1, CBR3) across the biochemical pathway of doxorubicin in Asian breast cancer patients receiving doxorubicin based adjuvant chemotherapy. The influence of functional genetic variants on the inter-individual variability in pharmacokinetics of doxorubicin and its major metabolite are also discussed. The incorporation of non-genetic factors and subsequent validation of these findings in different patient and population groups will be valuable in tailoring doxorubicin dosage regimens to an individual to maximize therapeutic efficacy and minimize adverse reactions, leading to improved clinical outcomes.

The Synergistic Effect of Doxorubicin and Ethanolic Extracts of Caesalpinia sappan L. Wood and Ficus septica Burm. f. Leaves on Viability, Cell Cycle Progression, and Apoptosis Induction of MCF­7 Cells

“…Currently, these agents are combined with conventional chemotherapeutic agent to overcome cell cycle mediated drug resistance and to enhance cytotoxic efficacy (Kelley et al, 2014). Doxorubicin modulates cell cycle through G1 and G2 phases arrest, as the result of its interaction with topoisomerase II mediated DNA damage (Lal et al, 2010). Our result confirmed that single treatment of dox 2 µM and ECS 16 µg/ml induced cell accumulation at G2/M phase.…”

Cardiovascular Disease

“…49 A detailed discussion of these differences are beyond the scope of this review; for additional information, see the review by Lal et al and references therein. 49 It has been hypothesized that cardiotoxicity of anthracyclines is more severe in the setting of increased ROS. Genes that regulate the NADPH oxidase complex, which is involved with ROS generation, may potentially have an effect on cardiotoxicity.…”

“…Interindividual differences and interethnic variability in processing and detoxifying anthracycline may lead to differing severity of cardiotoxicity. 49 A detailed discussion of these differences are beyond the scope of this review; for additional information, see the review by Lal et al and references therein. 49 It has been hypothesized that cardiotoxicity of anthracyclines is more severe in the setting of increased ROS.…”

Inhibition of Migration and Invasion of LNCap Human Prostate Carcinoma Cells by Doxorubicin through Inhibition of Matrix Metalloproteinase Activity and Tightening of Tight Junctions

“…Doxorubicin은 DNA 염기 서열 사이에 삽입되어 DNA 구조 손상을 유발하여 세포 분열을 차단시킴으로서 강력한 항암 활성을 나타내지만, 백혈 구 감소증, 빈혈, 심장 기능 상실 등의 부작용이 나타나기도 한다. Doxorubicin은 단일 항암제로도 널리 사용이 되지만, 항암활성의 상승과 부작용의 최소화를 위하여 다른 항암제와 복합 처리하여 사용되기도 한다 [10]. Doxorubicin이 암세포의 증식 억제 측면에서 세포주기 교란 [18,30] 및 세포사멸 유도 [6,28]를 포함한 전이 억제 효과 [5,14,27] 등은 이미 잘 알려진 사실이지만, 전립선 암세포에서의 전이 억제 관련 기전 연구 는 여전히 미비한 실정이다.…”