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Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity

Jabir RS, Naidu R, Annuar MA, Ho GF, Munisamy M, Stanslas J

Pharmacogenomics, 2012 Dec;13(16):1979-88.
PMID: 23215890 DOI: 10.2217/pgs.12.165

Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

Matched MeSH terms: Paclitaxel/therapeutic use
Targeted delivery of paclitaxel drug using polymer-coated magnetic nanoparticles for fibrosarcoma therapy: in vitro and in vivo studies

Al-Obaidy R, Haider AJ, Al-Musawi S, Arsad N

Sci Rep, 2023 Feb 23;13(1):3180.
PMID: 36823237 DOI: 10.1038/s41598-023-30221-x

Fibrosarcoma is a rare type of cancer that affects cells known as fibroblasts that are malignant, locally recurring, and spreading tumor in fibrous tissue. In this work, an iron plate immersed in an aqueous solution of double added deionized water, supplemented with potassium permanganate solution (KMnO4) was carried out by the pulsed laser ablation in liquid method (PLAIL). Superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized using different laser wavelengths (1064, 532, and 266 nm) at a fluence of 28 J/cm2 with 100 shots of the iron plate to control the concentration, shape and size of the prepared high-stability SPIONs. The drug nanocarrier was synthesized by coating SPION with paclitaxel (PTX)-loaded chitosan (Cs) and polyethylene glycol (PEG). This nanosystem was functionalized by receptors that target folate (FA). The physiochemical characteristics of SPION@Cs-PTX-PEG-FA nanoparticles were evaluated and confirmed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-Ray diffraction (XRD), atomic force microscopy (AFM), and dynamic light scattering (DLS) methods. Cell internalization, cytotoxicity assay (MTT), apoptosis induction, and gene expression of SPION@Cs-PTX-PEG-FA were estimated in fibrosarcoma cell lines, respectively. In vivo studies used BALB/c tumor-bearing mice. The results showed that SPION@Cs-PTX-PEG-FA exhibited suitable physical stability, spherical shape, desirable size, and charge. SPION@Cs-PTX-PEG-FA inhibited proliferation and induced apoptosis of cancer cells (P

Matched MeSH terms: Paclitaxel/therapeutic use
Modeling and development of screen-printed impedance biosensor for cytotoxicity studies of lung carcinoma cells

Mansor AFM, Ibrahim I, Zainuddin AA, Voiculescu I, Nordin AN

Med Biol Eng Comput, 2018 Jan;56(1):173-181.
PMID: 29247387 DOI: 10.1007/s11517-017-1756-1

Electrical cell-substrate impedance sensing (ECIS) is a powerful technique to monitor real-time cell behavior. In this study, an ECIS biosensor formed using two interdigitated electrode structures (IDEs) was used to monitor cell behavior and its response to toxicants. Three different sensors with varied electrode spacing were first modeled using COMSOL Multiphysics and then fabricated and tested. The silver/silver chloride IDEs were fabricated using a screen-printing technique and incorporated with polydimethylsiloxane (PDMS) cell culture wells. To study the effectiveness of the biosensor, A549 lung carcinoma cells were seeded in the culture wells together with collagen as an extracellular matrix (ECM) to promote cell attachment on electrodes. A549 cells were cultured in the chambers and impedance measurements were taken at 12-h intervals for 120 h. Cell index (CI) for both designs were calculated from the impedance measurement and plotted in comparison with the growth profile of the cells in T-flasks. To verify that the ECIS biosensor can also be used to study cell response to toxicants, the A549 cells were also treated with anti-cancer drug, paclitaxel, and its responses were monitored over 5 days. Both simulation and experimental results show better sensitivity for smaller spacing between electrodes. Graphical abstract The fabricated impedance biosensor used screen-printed silver/silver chloride IDEs. Simulation and experimental results show better sensitivity for smaller between electrodes.

Matched MeSH terms: Paclitaxel/therapeutic use
Third S. S. Ratnam memorial lecture 2007. Ovarian cancer: Is there hope for women?

Sivanesaratnam V

J Obstet Gynaecol Res, 2009 Jun;35(3):393-404.
PMID: 19527374 DOI: 10.1111/j.1447-0756.2009.01049.x

Ovarian cancer is today the most lethal female cancer with an overall survival of only 49.9%. The currently available screening modalities are disappointing in detecting highly curable early stage ovarian cancer. Natural history of ovarian cancer is unknown; it appears it can develop quickly from normal looking ovaries. Timely referral of women with non-specific symptoms (such as abdominal bloating, pelvic pain) for an ultrasound scan or blood CA125 assessments may help in the early diagnosis. Patients with Stage IA or IB disease with grade 1 tumors have a cure rate of >90%; this is likely to be compromised by laparoscopic surgery. In selected patients fertility preservation with good obstetric outcome is possible. However, the relapse rate in 'high risk' early stage ovarian cancers is 40-45%; adjuvant chemotherapy is needed. Only 20-25% of those with stage III and IV disease are cured. Despite a high primary response (70%) majority (70-75%) will relapse and all are likely to succumb. Optimal debulking surgery followed by adjuvant chemotherapy are needed for stages III and IV disease; the outcome is superior if managed by gynecologic oncologists. Where cost of drugs is an important consideration, an alternative is carboplatin (an affordable and equally effective drug). The role of vaccines needs further study. When relapses occur palliation will be the aim in most instances. Oral contraceptives, breast feeding, tubal sterilization and hysterectomy also have a protective effect. Risk-reducing salpingo-oopherectomy has been suggested in women with BRCA mutations.

Matched MeSH terms: Paclitaxel/therapeutic use
A 35 Year Old Bangladeshi Lady with Hereditary Mucinous Ovarian Cancer, Complicated with Omental Metastasis

Islam MJ, Roshid B, Pervin S, Kabir S, Chigurupati S, Hasan MN

Mymensingh Med J, 2019 Apr;28(2):484-489.
PMID: 31086172

Approximately 80% ovarian tumors are benign, and these arise mostly in young adult females. Malignant tumors are more prevalent in ageing women, between the ages of 45-65 years. Mucinous ovarian cancer represents about 5% of epithelial ovarian cancers (EOC). We have reported a case of mucinous cystadenocarcinoma in 35-year-old lady with metastasis to momentum. Imaging (Radiograph & CT scan) studies showed a large right sided pelvic mass with probable origin in the right ovary. Cancer antigen-125 was elevated, while carcinoembrionic antigen and alpha-fetoprotein were normal. Mutational profiles shown distinct finding, as KRAS mutations positive nevertheless p53 and BRCA mutations are absent. She had undergone total abdominal hysterectomy with bilateral salphingo-oopherectomy along with pelvic dissection for removal of lymph nodes at the age of 35. She was given 3 cycles of chemotherapy with cisplatin and paclitaxel. To the best of our knowledge, this is the one of the little cases of ovarian mucinous cystadenocarcinoma being reported at a relatively young age and the first case being reported from Bangladesh.

Matched MeSH terms: Paclitaxel/therapeutic use*
Antiproliferative activity of ionic liquid-graviola fruit extract against human breast cancer (MCF-7) cell lines using flow cytometry techniques

Daddiouaissa D, Amid A, Kabbashi NA, Fuad FAA, Elnour AM, Epandy MAKMS

J Ethnopharmacol, 2019 May 23;236:466-473.
PMID: 30853648 DOI: 10.1016/j.jep.2019.03.003

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants have been used for ages by indigenous communities around the world to help humankind sustain its health. Graviola (Annona muricata), also called soursop, is a member of the Annonaceae family and is an evergreen plant that is generally distributed in tropical and subtropical areas of the world. Graviola tree has a long history of traditional use due to its therapeutic potential including anti-inflammatory, antimicrobial, antioxidant, insecticide and cytotoxic to tumor cells.
AIM OF THE STUDY: This study aimed to investigate the in vitro antiproliferative effects and apoptotic events of the ionic liquid extract of Graviola fruit (IL-GFE) on MCF-7 breast cancer cells and their cytokinetics behaviour to observe their potential as a therapeutic alternative in cancer treatment.
MATERIALS AND METHODS: The cell viability assay of the extract was measured using tetrazolium bromide (MTT assay) to observe the effects of Graviola fruit extract. Then the cytokinetics behaviour of MCF-7 cells treated with IL-GFE is observed by plotting the growth curve of the cells. Additionally, the cell cycle distribution and apoptosis mechanism of IL-GFE action on MCF-7 cancer cells were observed by flow cytometry.
RESULTS: IL-GFE exhibited anti-proliferative activity on MCF-7 with the IC50 value of 4.75 μg/mL, compared to Taxol with an IC50 value of 0.99 μg/mL. IL- GFE also reduced the number of cell generations from 3.71 to 1.67 generations compared to 2.18 generations when treated with Taxol. Furthermore, the anti-proliferative activities were verified when the growth rate was decreased dynamically from 0.0077 h to 1 to 0.0035 h-1. Observation of the IL-GFE-treated MCF-7 under microscope demonstrated detachment of cells and loss of density. The growth inhibition of the cells by extracts was associated with cell cycle arrest at the G0/G1 phase, and phosphatidylserine externalisation confirms the anti-proliferation through apoptosis.
CONCLUSIONS: ionic liquid Graviola fruit extract affect the cytokinetics behaviour of MCF-7 cells by reducing cell viability, induce apoptosis and cell cycle arrest at the G0/G1 phase.

Matched MeSH terms: Paclitaxel/therapeutic use
Alpha-tomatine synergises with paclitaxel to enhance apoptosis of androgen-independent human prostate cancer PC-3 cells in vitro and in vivo

Lee ST, Wong PF, Hooper JD, Mustafa MR

Phytomedicine, 2013 Nov 15;20(14):1297-305.
PMID: 23920276 DOI: 10.1016/j.phymed.2013.07.002

Alpha (α)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of α-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub-toxic dose of α-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro-apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and α-tomatine may be beneficial for refractory prostate cancer treatment.

Matched MeSH terms: Paclitaxel/therapeutic use*