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 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 MDR cancers before clinical failure has the potential to offer new approaches to fighting MDR cancer.
Highlights
Of the many scientific advances made in our lifetime, effective cancer treatment and control still remains elusive
Three subfamilies have been identified as relevant for multiple drug resistance (MDR): MDR-1 (ABCB1) and BCRP (ABCG2) predominantly pump large hydrophobic, positively charged amphiphilic compounds including major chemotherapeutic agents used in breast cancer (e.g., DOX, mitoxantrone, or verapamil) out of the cell, while the multidrug resistance proteins (MRPs) found in the ABCC subfamily, drive out hydrophobic uncharged molecules, as well as water-soluble anionic compounds [19]
TFPI1 overexpression is not specific to the MCF7 cell lines that have undergone selection for resistance to DOX, as we have demonstrated that TFPI1 protein levels were elevated in all MDR cells tested, including human K562 myelogenous leukemia cells and human colon adenocarcinoma Colo201 cells we selected for DOX resistance, and rat glioblastoma treatment sensitive and resistant C6 and F98 cells, respectively [64]
Summary
Of the many scientific advances made in our lifetime, effective cancer treatment and control still remains elusive. Malignancies of the breast are an example of a common cancer that frequently returns years after initial therapy, but in a treatment-resistant form, despite the combined use of aggressive adjuvant and neoadjuvant approaches [3,4,5,6]. These tumors display a confounding multiple drug resistance (MDR) [7]. Given the recurrence rate of treatment-resistant breast tumors and the limited number of therapies available, there is clearly both need and urgency to find novel strategies, early detection, and efficient reversal of MDR cancers
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