Special Issue "Drug/Radiation Resistance in Cancer Therapy"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 September 2015)

Special Issue Editors

Guest Editor
Dr. Zhe-Sheng (Jason) Chen

Department of Pharmaceutical Sciences, St. John's University, Queens, USA
Website | E-Mail
Interests: Drug Resistance; ABC transporters; Cancer Chemotherapy; Natural Products; Nanomaterials
Guest Editor
Dr. Dong-Hua Yang

Department of Pharmaceutical Sciences, St. John's University, Queens, USA
E-Mail
Interests: Biomarkers; Anti-Cancer Drugs; Cancer Chemotherapy; Cancer Biology; Developmental Biology

Special Issue Information

Dear Colleagues,

The phenomenon of drug and/or radiation resistance has attenuated the efficacy of chemotherapeutic agents as well as radiotherapy, and reduced the possibility of successful cancer treatment. Progress has been made in recent years in understanding many of the resistant mechanisms, and of methods to overcome resistance. Scientists have elucidated that Multidrug Resistance (MDR) is a major obstacle to cancer treatment, which can be induced by anticancer drugs and ionizing radiation. The most common mechanisms that produce MDR in cancer cells include: (1) altered cell cycle check points; (2) induction of emergency response genes; (3) enhanced DNA repair; (4) alterations in membrane proteins or lipids; (5) compartmentalization; (6) inhibition of apoptosis; (7) altered drug targets; (8) decreased uptake; and (9) increased efflux of drugs by ATP-binding cassette (ABC) transporters.

Among the ABC transporters family, ABCB1, ABCG2, and ABCCs are the primary contributors of MDR in cancer cells. Interestingly, the overexpression of ABCB1 has been associated with various cancers, such as gastrointestinal stromal tumor (GIST), non-small cell lung cancer (NSCLC), and ovarian and thyroid cancers. It has also been shown that increased resistance to both chemotherapy and radiation is a feature of Cancer Stem-like Cells (CSCs): the subset of cells within a tumor that have the ability to drive tumor re-growth or to initiate a metastatic lesion. ABCG2 is implicated as a CSC biomarker in diverse malignancies.

This Special Issue will cover subjects related to recent progress on drug and radiation resistance in cancer therapy. It will increase our understanding of the clinical efficacy and challenges of chemotherapy and radiotherapy in a variety of cancers.

Prof. Dr. Zhe-Sheng (Jason) Chen
Dr. Dong-Hua (Hana) Yang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multidrug resistance
  • chemotherapy
  • radiotherapy
  • ABC transporters
  • cancer stem-like cells
  • biomarkers

Published Papers (10 papers)

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Research

Jump to: Review

Open AccessArticle Computed Tomography Demonstration of the Production and Distribution of Oxygen Gas Following Intratumoral Injection of a New Radiosensitizer (KORTUC) for Patients with Breast Cancer—Is Intratumoral Injection Not an Ideal Approach to Solve the Major Problem of Tumor Hypoxia in Radiotherapy?
Received: 26 January 2016 / Revised: 16 March 2016 / Accepted: 28 March 2016 / Published: 1 April 2016
Cited by 3 | PDF Full-text (2695 KB) | HTML Full-text | XML Full-text
Abstract
We previously developed a new enzyme-targeting radiosensitization treatment named Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate for injection into various types of tumors. For breast cancer treatment, the radiosensitization agent was injected into [...] Read more.
We previously developed a new enzyme-targeting radiosensitization treatment named Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate for injection into various types of tumors. For breast cancer treatment, the radiosensitization agent was injected into the tumor tissue twice a week under ultrasonographic guidance, immediately prior to each administration of radiation therapy. At approximately three hours after the second or third injection, computed tomography (CT) was performed to confirm the production and distribution of oxygen gas generated from the KORTUC radiosensitization agent by catalysis of peroxidases contained mainly in tumor tissue. The purpose of this study was to demonstrate that tumor hypoxia could be overcome by such a procedure and to evaluate the method of intratumoral injection in terms of confirming oxygen distribution in the target tumor tissue and around the tumor to be visualized on dedicated CT imaging. Three-dimensional reconstructed maximum intensity projection imaging of contrast-enhanced breast magnetic resonance imaging was used to compare the position of the tumor and that of the generated oxygen. Distributed oxygen gas was confirmed in the tumor tissue and around it in all 10 patients examined in the study. A region of oxygen gas was measured as an average value of −457.2 Hounsfield units (HU) as a region of interest. A slightly increased HU value compared to the density of air or oxygen was considered due to the presence of tumor tissue in the low-density area on 5-mm-thick reconstructed CT imaging. The results of this study showed that intratumoral oxygen was successfully produced by intratumoral KORTUC injection under ultrasonographic guidance, and that tumor hypoxia, which is considered a main cause of radioresistance in currently used Linac (linear accelerator) radiation therapy for malignant neoplasms, could be resolved by this method. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessArticle Development of a Novel Enzyme-Targeting Radiosensitizer (New KORTUC) Using a Gelatin-Based Hydrogel Instead of a Sodium Hyaluronate
Received: 28 October 2015 / Revised: 4 January 2016 / Accepted: 5 January 2016 / Published: 7 January 2016
Cited by 3 | PDF Full-text (775 KB) | HTML Full-text | XML Full-text
Abstract
We recently developed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) as a strategy to increase intratumoral oxygen concentrations and degrade antioxidant enzymes such as peroxidase and catalase. We then developed KORTUC II, which uses sodium hyaluronate containing hydrogen peroxide as a radiosensitizer. KORTUC [...] Read more.
We recently developed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) as a strategy to increase intratumoral oxygen concentrations and degrade antioxidant enzymes such as peroxidase and catalase. We then developed KORTUC II, which uses sodium hyaluronate containing hydrogen peroxide as a radiosensitizer. KORTUC II requires twice-weekly administration to sustain its effects, but decreasing the frequency of radiosensitizer injections to once-weekly would reduce the burden on the patients and the physicians. The goal of this study was thus to develop a new formulation of KORTUC (New KORTUC) that only requires once-weekly administration. We performed experimental studies using a mouse tumor model and biodegradable hydrogel. C3H/He mice were allocated to control, KORTUC, or hydrogel groups. At 72 h after injection, each tumor was irradiated with a 6 MeV electron beam to a total dose of 30 Gy. During a 62-day observation period, changes in tumor volume and survival rates were assessed in each group. Tumor growth rate was slowest in the hydrogel groups. These data suggest that hydrogel could represent a useful adjunct as a long-acting radiosensitizer in place of sodium hyaluronate. New KORTUC, which contains hydrogen peroxide and hydrogel, exerted a radiosensitizing effect that persisted beyond 72 h following injection of the agent. Use of this new formulation allows radiosensitizer injections to be performed once-weekly with good effect. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessArticle Serial Assessment of Therapeutic Response to a New Radiosensitization Treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), in Patients with Stage I/II Breast Cancer Using Breast Contrast-Enhanced Magnetic Resonance Imaging
Received: 1 October 2015 / Revised: 16 December 2015 / Accepted: 16 December 2015 / Published: 22 December 2015
Cited by 8 | PDF Full-text (3501 KB) | HTML Full-text | XML Full-text
Abstract
Background: We have developed a new radiosensitization treatment called Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II). Using KORTUC II, we performed breast-conserving treatment (BCT) without any surgical procedure for elderly patients with breast cancer in stages I/II or patients refusing [...] Read more.
Background: We have developed a new radiosensitization treatment called Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II). Using KORTUC II, we performed breast-conserving treatment (BCT) without any surgical procedure for elderly patients with breast cancer in stages I/II or patients refusing surgery. Since surgery was not performed, histological confirmation of the primary tumor region following KORTUC II treatment was not possible. Therefore, to precisely evaluate the response to this new therapy, a detailed diagnostic procedure is needed. The goal of this study was to evaluate the therapeutic response to KORTUC II treatment in patients with stage I/II breast cancer using annual breast contrast-enhanced (CE) magnetic resonance imaging (MRI). Methods: Twenty-one patients with stage I/II breast cancer who were elderly and/or refused surgery were enrolled in this study. All patients underwent MRI prior to and at 3 to 6 months after KORTUC II, and then approximately biannually thereafter. Findings from MRI were compared with those from other diagnostic modalities performed during the same time period. Results: KORTUC II was well tolerated, with minimal adverse effects. All of 21 patients showed a clinically complete response (cCR) on CE MRI. The mean period taken to confirm cCR on the breast CE MRI was approximately 14 months. The mean follow-up period for the patients was 61.9 months at the end of October 2014. Conclusions: The therapeutic effect of BCT using KORTUC II without surgery could be evaluated by biannual CE MRI evaluations. Approximately 14 months were required to achieve cCR in response to this therapy. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessArticle Non-Surgical Breast-Conserving Treatment (KORTUC-BCT) Using a New Radiosensitization Method (KORTUC II) for Patients with Stage I or II Breast Cancer
Cancers 2015, 7(4), 2277-2289; https://doi.org/10.3390/cancers7040891
Received: 30 September 2015 / Revised: 2 November 2015 / Accepted: 4 November 2015 / Published: 17 November 2015
Cited by 8 | PDF Full-text (1328 KB) | HTML Full-text | XML Full-text
Abstract
The purpose of the present study was to establish a non-surgical breast-conserving treatment (BCT) using KORTUC II radiosensitization treatment. A new radiosensitizing agent containing 0.5% hydrogen peroxide and 0.83% sodium hyaluronate (a CD44 ligand) has been developed for intra-tumoral injection into various tumors. [...] Read more.
The purpose of the present study was to establish a non-surgical breast-conserving treatment (BCT) using KORTUC II radiosensitization treatment. A new radiosensitizing agent containing 0.5% hydrogen peroxide and 0.83% sodium hyaluronate (a CD44 ligand) has been developed for intra-tumoral injection into various tumors. This new method, named KORTUC II, was approved by our local ethics committee for the treatment of breast cancer and metastatic lymph nodes. A total of 72 early-stage breast cancer patients (stage 0, 1 patient; stage I, 23; stage II, 48) were enrolled in the KORTUC II trial after providing fully informed consent. The mean age of the patients was 59.7 years. A maximum of 6 mL (usually 3 mL for tumors of less than approximately 3 cm in diameter) of the agent was injected into breast tumor tissue twice a week under ultrasonographic guidance. For radiotherapy, hypofraction radiotherapy was administered using a tangential fields approach including an ipsilateral axillary region and field-in-field method; the energy level was 4 MV, and the total radiation dose was 44 Gy administered as 2.75 Gy/fraction. An electron boost of 3 Gy was added three times. Treatment was well tolerated with minimal adverse effects in all 72 patients. No patients showed any significant complications other than mild dermatitis. A total of 24 patients under 75 years old with stage II breast cancer underwent induction chemotherapy (EC and/or taxane) prior to KORTUC II treatment, and 58 patients with estrogen receptor-positive tumors also received hormonal therapy following KORTUC II. The mean duration of follow-up as of the end of September 2014 was 51.1 months, at which time 68 patients were alive without any distant metastases. Only one patient had local recurrence and died of cardiac failure at 6.5 years. Another one patient had bone metastases. For two of the 72 patients, follow-up ended after several months following KORTUC II treatment. In conclusion, non-surgical BCT can be performed using KORTUC II, which has three major characteristics: imaging guidance; enzyme-targeting; and targeting of breast cancer stem cells via the CD44 receptor. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Review

Jump to: Research

Open AccessReview Radioresistance of Brain Tumors
Received: 17 January 2016 / Revised: 10 March 2016 / Accepted: 24 March 2016 / Published: 30 March 2016
Cited by 13 | PDF Full-text (767 KB) | HTML Full-text | XML Full-text
Abstract
Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the [...] Read more.
Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessReview South Asian Medicinal Compounds as Modulators of Resistance to Chemotherapy and Radiotherapy
Received: 18 January 2016 / Revised: 5 February 2016 / Accepted: 29 February 2016 / Published: 5 March 2016
Cited by 3 | PDF Full-text (1765 KB) | HTML Full-text | XML Full-text
Abstract
Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. During the last 30 years, extensive research has revealed much about the biology of cancer. Chemotherapy and radiotherapy are the mainstays of cancer treatment, particularly for patients [...] Read more.
Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. During the last 30 years, extensive research has revealed much about the biology of cancer. Chemotherapy and radiotherapy are the mainstays of cancer treatment, particularly for patients who do not respond to surgical resection. However, cancer treatment with drugs or radiation is seriously limited by chemoresistance and radioresistance. Various approaches and strategies are employed to overcome resistance to chemotherapy and radiation treatment. Many plant-derived phytochemicals have been investigated for their chemo- and radio-sensitizing properties. The peoples of South Asian countries such as India, Pakistan, Sri Lanka, Nepal, Bangladesh and Bhutan have a large number of medicinal plants from which they produce various pharmacologically potent secondary metabolites. The medicinal properties of these compounds have been extensively investigated and many of them have been found to sensitize cancer cells to chemo- and radio-therapy. This review focuses on the role of South Asian medicinal compounds in chemo- and radio-sensitizing properties in drug- and radio-resistant cancer cells. Also discussed is the role of South Asian medicinal plants in protecting normal cells from radiation, which may be useful during radiotherapy of tumors to spare surrounding normal cells. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessReview Paradigm Shift in Radiation Biology/Radiation Oncology—Exploitation of the “H2O2 Effect” for Radiotherapy Using Low-LET (Linear Energy Transfer) Radiation such as X-rays and High-Energy Electrons
Received: 8 December 2015 / Revised: 17 February 2016 / Accepted: 22 February 2016 / Published: 25 February 2016
Cited by 8 | PDF Full-text (2589 KB) | HTML Full-text | XML Full-text
Abstract
Most radiation biologists/radiation oncologists have long accepted the concept that the biologic effects of radiation principally involve damage to deoxyribonucleic acid (DNA), which is the critical target, as described in “Radiobiology for the Radiologist”, by E.J. Hall and A.J. Giaccia [1]. Although the [...] Read more.
Most radiation biologists/radiation oncologists have long accepted the concept that the biologic effects of radiation principally involve damage to deoxyribonucleic acid (DNA), which is the critical target, as described in “Radiobiology for the Radiologist”, by E.J. Hall and A.J. Giaccia [1]. Although the concepts of direct and indirect effects of radiation are fully applicable to low-LET (linear energy transfer) radioresistant tumor cells/normal tissues such as osteosarcoma cells and chondrocytes, it is believed that radiation-associated damage to DNA does not play a major role in the mechanism of cell death in low-LET radiosensitive tumors/normal tissues such as malignant lymphoma cells and lymphocytes. Hall and Giaccia describe lymphocytes as very radiosensitive, based largely on apoptosis subsequent to irradiation. As described in this review, apoptosis of lymphocytes and lymphoma cells is actually induced by the “hydrogen peroxide (H2O2) effect”, which I propose in this review article for the first time. The mechanism of lymphocyte death via the H2O2 effect represents an ideal model to develop the enhancement method of radiosensitivity for radiation therapy of malignant neoplasms. In terms of imitating the high radiosensitivity of lymphocytes, osteosarcoma cells (representative of low-LET radioresistant cells) might be the ideal model for indicating the conversion of cells from radioresistant to radiosensitive utilizing the H2O2 effect. External beam radiation such as X-rays and high-energy electrons for use in modern radiotherapy are generally produced using a linear accelerator. We theorized that when tumors are irradiated in the presence of H2O2, the activities of anti-oxidative enzymes such as peroxidases and catalase are blocked and oxygen molecules are produced at the same time via the H2O2 effect, resulting in oxidative damage to low-LET radioresistant tumor cells, thereby rendering them highly sensitive to irradiation. In this review, this potential paradigm shift in modern radiation biology/radiation oncology is discussed in detail in terms of overcoming drug/radiation resistance in radiation therapy and/or anti-cancer chemotherapy. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessReview Cancer Stem Cell Plasticity Drives Therapeutic Resistance
Received: 19 October 2015 / Revised: 18 December 2015 / Accepted: 29 December 2015 / Published: 5 January 2016
Cited by 48 | PDF Full-text (778 KB) | HTML Full-text | XML Full-text
Abstract
The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The [...] Read more.
The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessFeature PaperReview Paclitaxel Through the Ages of Anticancer Therapy: Exploring Its Role in Chemoresistance and Radiation Therapy
Cancers 2015, 7(4), 2360-2371; https://doi.org/10.3390/cancers7040897
Received: 1 October 2015 / Revised: 24 November 2015 / Accepted: 30 November 2015 / Published: 3 December 2015
Cited by 50 | PDF Full-text (421 KB) | HTML Full-text | XML Full-text
Abstract
Paclitaxel (Taxol®) is a member of the taxane class of anticancer drugs and one of the most common chemotherapeutic agents used against many forms of cancer. Paclitaxel is a microtubule-stabilizer that selectively arrests cells in the G2/M phase of the cell [...] Read more.
Paclitaxel (Taxol®) is a member of the taxane class of anticancer drugs and one of the most common chemotherapeutic agents used against many forms of cancer. Paclitaxel is a microtubule-stabilizer that selectively arrests cells in the G2/M phase of the cell cycle, and found to induce cytotoxicity in a time and concentration-dependent manner. Paclitaxel has been embedded in novel drug formulations, including albumin and polymeric micelle nanoparticles, and applied to many anticancer treatment regimens due to its mechanism of action and radiation sensitizing effects. Though paclitaxel is a major anticancer drug which has been used for many years in clinical treatments, its therapeutic efficacy can be limited by common encumbrances faced by anticancer drugs. These encumbrances include toxicities, de novo refraction, and acquired multidrug resistance (MDR). This article will give a current and comprehensive review of paclitaxel, beginning with its unique history and pharmacology, explore its mechanisms of drug resistance and influence in combination with radiation therapy, while highlighting current treatment regimens, formulations, and new discoveries. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessReview Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1
Cancers 2015, 7(4), 2063-2082; https://doi.org/10.3390/cancers7040877
Received: 11 September 2015 / Accepted: 10 October 2015 / Published: 16 October 2015
Cited by 12 | PDF Full-text (834 KB) | HTML Full-text | XML Full-text
Abstract
Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have [...] Read more.
Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have included anthracyclines such as Doxorubicin (DOX); and its use in aggressive tumors appears to remain a viable option; but drug resistance arises against DOX; as for all other classes of compounds. Our recent work suggests the anticoagulant protein Tissue Factor Pathway Inhibitor 1α (TFPI1α) plays a role in driving the development of multiple drug resistance (MDR); but not maintenance; of the MDR state. Other factors; such as the ABC transporter drug efflux pumps MDR-1/P-gp (ABCB1) and BCRP (ABCG2); are required for MDR maintenance; as well as development. The patient population struggling with therapeutic resistance specifically requires novel treatment options to resensitize these tumor cells to therapy. In this review we discuss the development, maintenance, and reversal of MDR as three distinct phases of cancer biology. Possible means to exploit these stages to reverse MDR will be explored. Early molecular detection of MDRcancers before clinical failure has the potential to offer new approaches to fighting MDRcancer. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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