Pharmacodynamic considerations in the use of matrix metalloproteinase inhibitors in cancer treatment

Abstract

Introduction: Matrix metalloproteinases (MMPs) are classified in the family of zinc-dependent endopeptidases, which can degrade various components of an extracellular matrix and a basement membrane. Studies have demonstrated that MMPs relate to the development of malignant tumors and induce angiogenesis, resulting in the invasion and metastasis of tumor cells. MMPs are highly expressed in malignant tumors and are related to cancer patients’ malignant phenotype and poor prognosis. Therefore, blocking the expression or activity of MMPs may be a promising strategy for cancer treatment.
Areas Covered: This study aimed to explain the MMP structure, regulatory mechanism, and carcinogenic effect; investigate the matrix metalloproteinase-inhibitors (MMPIs) that are currently used in clinical trials for cancer treatment; and summarize the trial results.
Expert Opinion: Currently, the results of clinical trials that have used MMPIs as anticancer agents are unsatisfactory. However, MMPs remain an attractive target for cancer treatment. For example, development of the specific peptide or antibodies in targeting the hemopexin domain of MMP-2 may be a new therapeutic direction. The design and development of MMPIs that have selectivity will be the primary focus in future studies.

Full text

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REVIEW
Pharmacodynamic considerations in the use of matrix metalloproteinase
inhibitors in cancer treatment
Jia-Sin Yang
a,b
, Chiao-Wen Lin
c,d
, Shih-Chi Su
e,f
and Shun-Fa Yang
a,b
a
Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan;
b
Institute of Medicine, Chung Shan Medical
University, Taichung, Taiwan;
c
Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan;
d
Department of Dentistry,
Chung Shan Medical University Hospital, Taichung, Taiwan;
e
Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung
Memorial Hospital, Keelung, Taiwan;
f
Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung
Memorial Hospitals, Linkou, Taiwan
ABSTRACT
Introduction: Matrix metalloproteinases (MMPs) are classified in the family of zinc-dependent
endopeptidases, which can degrade various components of an extracellular matrix and a base-
ment membrane. Studies have demonstrated that MMPs relate to the development of malignant
tumors and induce angiogenesis, resulting in the invasion and metastasis of tumor cells. MMPs
are highly expressed in malignant tumors and are related to cancer patients’malignant pheno-
type and poor prognosis. Therefore, blocking the expression or activity of MMPs may be a
promising strategy for cancer treatment.
Areas Covered: This study aimed to explain the MMP structure, regulatory mechanism, and
carcinogenic effect; investigate the matrix metalloproteinase-inhibitors (MMPIs) that are currently
used in clinical trials for cancer treatment; and summarize the trial results.
Expert Opinion: Currently, the results of clinical trials that have used MMPIs as anticancer agents
are unsatisfactory. However, MMPs remain an attractive target for cancer treatment. For example,
development of the specific peptide or antibodies in targeting the hemopexin domain of MMP-2
may be a new therapeutic direction. The design and development of MMPIs that have selectivity
will be the primary focus in future studies.
ARTICLE HISTORY
Received 29 September 2015
Accepted 10 December 2015
Published online
8 January 2016
KEYWORDS
Cancer; matrix
metalloproteinases; matrix
metalloproteinases inhibitor;
pharmacodynamics
1. Introduction
Cancer has been detected for years and remains a
major threat to the health of human beings worldwide.
According to GLOBOCAN 2012, the global incidence of
cancer was 14,067,894 persons, and the global mortality
was 8,201,575 persons.[1] The United States estimated
that 1,658,370 new cancer cases and 589,430 deaths
caused by cancer would occur in 2015.[2] Despite the
advanced medical technology that renders cancer a
curable disease, the mortality rate of cancer remains
high. Cancer has the following characteristics: (1) sus-
taining proliferative signaling, (2) evading growth sup-
pressors, (3) resisting cell death, (4) enabling replicative
immortality, (5) inducing angiogenesis, and (6) activat-
ing invasion and metastasis.[3] Cancer metastasis and
invasion are crucial causes of the high mortality rate
and relate to the high expression of matrix metallopro-
teinases (MMPs).[4–6] MMPs are a group of proteinases,
which degrade and remodel extracellular matrix (ECM).
However, the high expression of MMPs is commonly
observed in various malignant tumors. In addition, the
MMP expression in the metastasis tissues is higher than
that in the primary tumor tissues.[7–9] Therefore, MMPs
play a vital role during the progression and metastasis
of malignant tumors. Designing and developing MMP
inhibitors (MMPIs) as anticancer agents is feasible for
cancer treatment.[10–12] Thus, this study discussed the
rationality of developing targeted therapy against
MMPs and summarized the use of MMPIs in clinical
trials and the results of these trials.
2. Matrix metalloproteinases
MMPs were first found in 1962 in the metamorphosis of
a tadpole tail. In 1968, MMPs were purified from human
skin. MMPs consist of zinc-dependent endopeptidases
and are synthesized from connective tissue cells and
proinflammatory cells, such as fibroblasts, osteoblasts,
endothelial cells, macrophages, neutrophils, and lym-
phocytes. Most MMPs are secreted in the form of unac-
tivated zymogen (pro-MMPs). The bait region on the
CONTACT Shun-Fa Yang ysf@csmu.edu.tw; Shih-Chi Su ssu1@cgmh.org.tw Institute of Medicine, Chung Shan Medical University, 110 Chien-Kuo
N. Road, Section 1, Taichung 402, Taiwan
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2016
VOL. 12, NO. 2, 191–200
http://dx.doi.org/10.1517/17425255.2016.1131820
© 2016 Taylor & Francis
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propeptide of MMPs is removed through hydrolysis by
serine proteases, furin, plasmin, or other MMP proteins.
Therefore, the MMPs are unstable. However, the MT-
MMPs are active and can, in turn, activate MMP-2. In
vitro investigations revealed that pro-MMP-2 (72 kDa)
activation requires contributions from MT1-MMP and
tissue inhibitor of metalloproteinase-2 (TIMP-2).[13]
Active MT1-MMP anchored to the cell surface acts as a
receptor for TIMP-2, which binds to the active site of
MT1-MMP. Subsequently, the interaction between the
cysteine on the propeptide and the Zn
2+
ions on the
catalytic domain is destroyed through a cysteine switch
mechanism, thus activating the MMPs.[14]
MMPs are typically classified into collagenases, gela-
tinases, stromelysins, and membrane-type MMPs (MT-
MMPs) according to the specificity of their substrates
and their location in cells. However, this classification
method is unsuitable for some MMPs. Therefore, the
MMPs are newly classified into archetypal MMPs, matri-
lysins, gelatinases, and furin-activatable MMPs accord-
ing to the domain organization of MMPs (Table 1).[15]
The basic structure of the archetypal MMPs involves a
signal peptide (approximately 20 amino acids), a pro-
peptide domain (approximately 80 amino acids) with a
cysteine-switch motif, a Zn
2+
-containing catalytic
domain (approximately 170 amino acids), and a hemo-
pexin domain (approximately 200 amino acids). The
hinge region (a linker peptide of variable length) is
connected to the catalytic domain. The archetypal
MMPs can be further divided into collagenases, strome-
lysins, and ‘other’according to the specificity of their
substrates. Collagenases include MMP-1 (collagenases-
1), MMP-8 (collagenases-2), and MMP-13 (collagenases-
3) and can lyse a collagen triple helix. Stromelysins
comprise MMP-3 (stromelysin-1) and MMP-10 (strome-
lysin-2) and have the same structure as that of collage-
nases. Stromelysins can degrade numerous ECM
components and activate procollagenases [16] and
proMMP-9 [17] but cannot degrade native collagen.
Other archetypal MMPs encompass MMP-12 (metalloe-
lastase), MMP-19, MMP-20 (enamelysin), and MMP-27,
which cannot be classified into collagenases or strome-
lysins because their sequence and substrate specificity
are different from that of the other two. Matrilysins
consist of MMP-7 (matrilysins-1) and MMP-26 (matrily-
sins-2) but lack the carboxy-terminal hemopexin
domain.[18] Gelatinases, involving MMP-2 (gelatinase-
A) and MMP-9 (gelatinase-B), have a fibronectin type II
motif in the catalytic domain and thus bind and
degrade denatured collagen or gelatin.[19] Furin-
activatable MMPs contain a furin recognition motif
between propeptide and the catalytic domain and can
be activated in cells through furin-like proteases. Furin-
activatable MMPs are classified into secreted MMPs, MT-
MMPs, and unusual type II transmembrane MMPs.
Secreted MMPs contain MMP-11 (stromelysin-3), MMP-
21, and MMP-28 (epilysin), which are secreted in an
activated form. MT-MMPs encompass membrane-
anchoring domains; therefore, they are located on the
cell surface to control the environment surrounding the
cells. According to the types of membranes to which
they adhere, MT-MMPs are divided into type I trans-
membrane MT-MMPs (involving MMP-14 [MT1-MMP],
MMP-15 [MT2-MMP], MMP-16 [MT3-MMP], and MMP-
24 [MT5-MMP]) and glycosylphosphatidylinositol MT-
MMPs (containing MMP-17 [MT4-MMP] and MMP-25
[MT6-MMP]).[20] Type II transmembrane MMPs contain
MMP-23A and MMP-23B, which have the same amino
acid sequence but originate from different human
genes. Type II transmembrane MMPs lack signal pep-
tide, cysteine-switch motif, or hemopexin domain but
contain a C-terminal tail with cysteine-array and immu-
noglobulin domains, and an N-terminal with type II
transmembrane domain. The activated MMPs generally
can degrade all the ECM and basement-membrane
components, including aggrecan, collagen, elastin,
fibronectin, gelatin, and laminin.[21] MMPs are indis-
pensable in embryonic development, angiogenesis,
cell growth, wound healing, and other physiological
development processes that require tissue remodeling.
[22,23] However, from a pathological perspective,
MMPs may facilitate the invasion of tumor cells into
connective tissues and blood vessel walls, resulting in
tumor metastasis.[24–26]
The activity of MMPs is controlled through the
mechanisms of gene expression, compartmentalization,
zymogen activation, and enzyme inhibition. The endo-
genous inhibitor of MMPs, namely α2-macroglobulin,
and the tissue inhibitors of metalloproteinases (TIMPs)
are primarily responsible for inhibiting MMPs [27,28]
and can also participate in MMP activation.[13] The
α2-macroglobulin is a large serum albumin, which
Article highlights.
●MMPs are classified in the family of zinc-dependent endopepti-
dases, which can degrade various components of an ECM and a
basement membrane.
●MMPs are highly expressed in malignant tumors and are related
to cancer patients’malignant phenotype and poor prognosis.
●Blocking the expression or activity of MMPs may be a promising
strategy for cancer treatment.
●MMPIs can be divided into four types: peptidomimetics, non-
peptidomimetics, tetracycline-like derivatives, and BPs.
●The failed application of MMPIs to cancer treatment may result
from their lack of selectivity for MMPs. Therefore, developing
MMPIs that have selectivity is a new direction for cancer treat-
ment.
This box summarizes key points contained in the article.
192 J.-S. YANG ET AL.
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Table 1. MMP family.
Domain composition
Enzyme group MMP
Chromosomal
location Substrates SP Pro CS RX[R/K]R Cat FNII LK1 Hpx LK2 TM GPI Cyt CyR-Ig
Archetypal MMPs
Collagenases
Collagenases-1 MMP-1 11q22.2–22.3 Collagen I, II, III, VII, VIII, X, XI, casein, perlecan,
entactin, laminin, proMMP-1, 2, 9, serpins
+ + + −+−++
Collagenases-2 MMP-8 11q22.2–22.3 Collagen I, II, III, VII, VIII, X, entactin, gelatin + + + −+−++
Collagenases-3 MMP-13 11q22.2–22.3 Collagen I, II, III, VII, X, XVIII, gelatin, entactin,
tenascin, aggregan
+ + + −+−++
Stromelysins
Stromelysin-1 MMP-3 11q22.2–22.3 Laminin, aggregan, gelatin, fibronectin + + + −+−++
Stromelysin-2 MMP-10 11q22.2–22.3 Collagen I, III, IV, gelatin, elastin, proMMP-1, 8,
10
+ + + −+−++
Other
Metalloelastase MMP-12 11q22.2–22.3 Elastin, gelatin, collagen I, IV, fibronectin,
laminin, vitronectin, proteoglycan
+ + + −+−++
Stromelysin-4 (RASI-1) MMP-19 12q14 Collagen I, IV, tenascin, gelatin, laminin + + + −+−++
Enamelysin MMP-20 11q22 Laminin, amelogenin, aggregan + + + −+−++
C-MMP MMP-27 11q24 –+ + + −+−++
Matrilysins
Matrilysins-1 MMP-7 11q22.2–22.3 Collagen I, IV, V, IX, X, XI, XVIII, fibronectin,
laminin, gelatin, aggregan, proMMP-9
+ + + −+− − −
Matrilysins-2 (endometase) MMP-26 11q22.2 Gelatin, collagen IV, proMMP-9 + + + −+− − −
Gelatinases
Gelatinase-A MMP-2 16q13 Gelatin, fibronectin, elastin, laminin, collagen
I, III, IV, V, VII, X, XI, vitronectin, decorin,
plasminogen
+ + + −+ + + +
Gelatinase-B MMP-9 20q11.2–q13.1 Gelatin, collagen I, IV, V, VII, X, XI, XVIII,
vitronectin, elastin, laminin, fibronectin,
proMMP-2, 9
+ + + −+ + + +
Furin-activatable MMPs
Secreted
Stromelysin-3 MMP-11 22q11.2 Fibronectin, laminin, aggregan, gelatin + + + + + −++
Epilysin MMP-28 17q11.2 Casein + + + + + −++
Type I transmembrane
MT1-MMP MMP-14 14q12.2 Collagen I, II, III, aggregan, laminin, gelatin,
proMMP-2, 13
+ + + + + −+ + + + −+
MT2-MMP MMP-15 16q12.2 Proteoglycans, proMMP-2 + + + + + −+ + + + −+
MT3-MMP MMP-16 8q21 Collagen III, fibronectin, proMMP-2 + + + + + −+ + + + −+
MT5-MMP MMP-24 20q11.2 Fibrinogen, gelatin, proMMP-2 + + + + + −+ + + + −+
GPI-anchored
MT4-MMP MMP-17 12q24 Gelatin, fibrinogen, proMMP-2 + + + + + −+++−+−
MT6-MMP (Leukolysin) MMP-25 16q13.3 Collagen IV, gelatin, proMMP-2, 9 + + + + + −+++−+−
Type II transmembrane
CA-MMP MMP-23 1p36.3 Gelatin ++−++− − − − − − − +
MMP: Matrix metalloproteinase; SP: Signal peptide; Pro: Propeptide domain; CS: Cysteine-switch motif; RX[R/K]R: Proprotein convertase recognition sequence; Cat: Catalytic domain; FNII: Fibronectin type II motif; LK:
Linker; Hpx: Hemopexin domain; TM: Transmembrane domain; GPI: Glycosylphophatidylinositol anchor; Cyt: Cytoplasmic tail domain; CyR-Ig: Cysteine-rich and immunoglobulin domain.
EXPERT OPINION ON DRUG METABO LISM & TOXICOLOGY 193
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partially regulates the activity of MMPs. It entraps MMPs
to prevent them from accessing substrates.[29] TIMPs
contain proteins related to TIMP-1, TIMP-2, TIMP-3, and
TIMP-4.[28,30] TIMPs are responsible for postactivation
inhibition of MMPs; they also participate in MMP activa-
tion, and regulate fibrosis and inflammation. Generally,
all TIMPs are capable of inhibiting all known MMPs;
however, the efficacy of MMP inhibition varies with
each TIMP. For example, TIMP-1 is a poor inhibitor of
MT1-MMP, MT3-MMP, MT5-MMP, and MMP-19. TIMP-2
is unique in that, in addition to inhibiting MMP activity,
it selectively interacts with MT1-MMP to facilitate the
cell-surface activation of proMMP-2. Moreover, TIMPs
and the active zinc-binding site of MMPs together
form noncovalent stoichiometric complexes to inhibit
the enzyme activity of MMPs.[31,32] MMPs play a criti-
cal role in the development of malignant tumors. When
the balance between TIMPs and MMPs is disturbed,
causing the MMP activity to increase, tissue degrada-
tion may occur in pathological states.[33,34] Thus, inhi-
biting MMPs can be a direction for cancer treatment.
Although the endogenous TIMPs can inhibit the patho-
logical activity of MMPs,[35] they are broad-spectrum
inhibitors and lack selectivity for individual MMPs. In
addition, TIMPs are involved in a number of physiolo-
gical processes that are not related to MMPs.[36–38]
Therefore, developing other MMPIs is vital.
3. Application of matrix metalloproteinase
inhibitors to cancer treatment
The importance of MMPs in cancer progression is
widely known. In the past 50 years, the medical field
has emphasized developing new MMPIs and investigat-
ing their application to cancer treatment. MMPIs can be
divided into four types: peptidomimetics, nonpeptido-
mimetics, tetracycline-like derivatives, and bisphospho-
nates (BPs). This study aimed to investigate the basic
and clinical application of the four types of MMPIs to
cancer treatment and the outcomes of such application
(Table 2).
3.1. Peptidomimetic matrix metalloproteinase
inhibitors
Peptidomimetic MMPIs are pseudopeptide derivatives
that simulate the active structure of MMPs.[39] They
reversibly bind to the active site of MMPs to chelate
zinc atoms.[40] Some zinc-binding groups, such as ami-
nocarboxylates, carboxylates, hydroxamates, sulfhy-
dryls, and derivatives of phosphoric acid, have been
tested for their effect on inhibiting MMP activity.
3.1.1 Hydroxamate derivatives
Hydroxamate derivatives, such as batimastat, marima-
stat, and solimastat, are the inhibitors most commonly
used in clinical practices. These hydroxamate inhibitors
are small peptide analogs of fibrillar collagens, which
inhibit MMP activity by interacting with Zn
2+
ions
located at the catalytic site of MMPs.
3.1.1.1 Batimastat (BB-94). Batimastat is a nonorally
bioavailable low-molecular-weight hydroxamate-based
inhibitor, which was the first MMPI used for clinical
trials.[41] Through directly binding to the Zn
2+
ions on
the MMP active site, batimastat inhibits the activity of
Table 2. Structure and MMP inhibition of synthetic MMPIs.
Class Compound Structure
Specificity
of the
inhibition
Peptidomimetic
MMPIs
Batimastat
(BB-94)
MMP-1, 2,
7, 9
Marimastat
(BB-2516)
MMP-1, 2,
3, 7, 9, 12
Solimastat
(BB-3644)
Broad-
spectrum
Nonpeptidomimetic
MMPIs
Prinomastat
(AG 3340)
MMP-2, 3,
7, 9, 13, 14
Tanomastat
(BAY
12–9566)
MMP-2, 3,
9, 13, 14
Rebimastat
(BMS-
275291)
MMP-1, 2,
3, 7, 9, 14
MMI-270
(CGS27023A)
MMP-1, 2, 3
Tetracycline
derivatives
Doxycycline MMP-2, 9
Metastat
(CMT-3; Col-
3)
MMP-1, 2,
8, 9, 13
Bisphosphonates Zoledronic
acid
(Zoledronate)
MMP-2, 9
MMP: Matrix metalloproteinase; MMPIs: Matrix metalloproteinase inhibitors.
194 J.-S. YANG ET AL.
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MMP-1, MMP-2, MMP-7, and MMP-9.[42] Batimastat
inhibits the growth of various cancer cell lines and has
no cytotoxicity in vitro.[43] Some in vivo studies have
verified the antitumor effect of batimastat in animal
models.[44–52] However, batimastat did not yield satis-
factory reactions in the phase I and II clinical trials, and
the trial was halted in phase III.[53] Because of its poor
solubility and low oral bioavailability, batimastat can
only be administered through intrapleural and intraper-
itoneal injection to assess cancer patients participating
in clinical trials.[41,54,55] However, this method has not
been widely accepted in cancer treatment.
3.1.1.2. Marimastat (BB-2516). Marimastat is a syn-
thetic MMPI with a low molecular weight and an orally
bioavailable MMPI that was first used for clinical trials
and can inhibit the activity of MMP-1, MMP-2, MMP-3,
MMP-7, MMP-9, and MMP-12. In the experimental
metastasis models of lung and breast cancer, marima-
stat reduced the number and size of the metastatic
lesions of the animals in the experimental and control
groups.[56] In clinical trials, marimastat exhibited ade-
quate efficacy in delaying disease progression.
However, because of limited dosage, the significance
of toxicity could not be determined. Patients using
marimastat experienced substantial musculoskeletal
pain and inflammation. Because no statistically signifi-
cant difference was observed between the trial results
regarding symptom deterioration and the overall survi-
val rate, the development of marimastat has been dis-
continued.[57]
3.1.1.3. Solimastat (BB-3644). Solimastat is an oral,
broad-spectrum MMPI; its structure is similar to that of
marimastat and batimastat. Currently, the inhibitory
activity of solimastat is still unknown. Although solima-
stat expresses anticancer characteristics similar to that
of marimastat, the phase I clinical trial that adminis-
tered solimastat to solid cancer failed.[58] Currently,
no further development and application of peptidomi-
metic MMPIs for cancer treatment have been
undertaken.
3.2. Nonpeptidomimetic matrix metalloproteinase
inhibitors
When used clinically, peptidomimetic MMPIs exhibited
problems of poor oral bioavailability (except for mari-
mastat) and lack of MMP specificity. To improve the
development of these drugs, some nonpeptidomimetic
MMPIs were synthesized according to the 3D X-ray
crystallography of the MMP active sites. Currently, the
nonpeptidomimetic MMPIs administered to cancer
patients for clinical assessment involve prinomastat
(AG 3340), tanomastat (BAY 12–9566), rebimastat
(BMS-275291), and MMI-270 (CGS27023A), which fea-
ture higher specificity and oral bioavailability than the
peptidomimetic MMPIs do.
3.2.1. Prinomastat (AG 3340)
Prinomastat is a synthetic, nonpeptidic collagen-
mimicking MMPI with a low molecular weight, which
can inhibit the activity of MMP-2, MMP-3, MMP-7, MMP-
9, MMP-13, and MMP-14. Studies using xenograft mod-
els have demonstrated the antitumor effect of prinoma-
stat.[59–64] Moreover, in a phase I and pharmacokinetic
study of prinomastat, Hande et al. found that prinoma-
stat was rapidly absorbed, with peak concentration
occurring within the first hour after dosing.[65]
However, in phase III trials, the application of prinoma-
stat combined with chemotherapy to the treatment of
advanced non-small-cell lung cancer failed to improve
the treatment efficacy.[66]
3.2.2. Tanomastat (BAY 12–9566)
Tanomastat is an orally bioavailable biphenyl synthetic
MMPI that can inhibit the activity of MMP-2, MMP-3,
MMP-9, MMP-13, and MMP-14.[67] An in vivo experi-
ment demonstrated that tanomastat can inhibit angio-
genesis.[68] A phase I and pharmacokinetic study of
tanomastat was tested, following 60 mg/m
2
infusion,
the mean peak plasma etoposide concentration was
11.7 ± 2.8 mg/ml.[69] Although tanomastat exhibited
satisfactory tolerance and generated no musculoskele-
tal side effects, it exhibited no reactions in phase I
clinical trials [70] and had no influence on the progres-
sion-free survival or overall survival rate in phase III
clinical trials.[71] The clinical development of tanoma-
stat has been terminated.
3.2.3. Rebimastat (BMS-275291)
Rebimastat is an orally bioavailable MMPI containing
thiol zinc-binding groups, which can inhibit the activity
of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-
14.[64] In a preclinical study, rebimastat inhibited tumor
progression in rodent tumor models.[72] Additionally,
in a phase I study, rebimastat did not exhibit dose-
limiting joint toxicity and no dose-limiting toxicities
occurred at 900, 1800, or 2400 mg/day.[73] The study
also found that the mean plasma concentration of rebi-
mastat at trough exceeded the calculated in vitro IC(80)
value for MMP-2 and IC(90) value for MMP-9 at the
recommended phase II dose of 1200 mg/day.[73]
However, rebimastat displayed an adverse effect in a
phase II trial on early stage breast cancer and a phase III
trial on non-small-cell lung carcinoma.[74,75]
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3.2.4. MMI-270 (CGS27023A)
MMI-270 is a broad-spectrum nonpeptidic hydroxamic
acid derivative MMPI that can inhibit MMP-1, MMP-2,
and MMP-3. In an in vitro experiment, MMI-270 could
not inhibit the proliferation of cancer cell lines but
could inhibit the invasion of tumor cells into Matrigel
and the angiogenesis of various preclinical models. In a
phase I clinical trial, the effect of MMI-270 on stabilizing
the disease progression was unsatisfactory. Moreover,
when a high dose of MMI-270 was administered, a
widespread maculopapular rash and musculoskeletal
side effects were observed.[76] Moreover, Eatock et al.
found that 5-fluorouracil (5-FU)/folinic acid with MMI-
270 at a dose of 300 mg twice daily is well tolerated;
however, MMI-270 has no significant effect on 5-FU
pharmacokinetics.[77] In a clinical trial on the treatment
of non-small-cell lung carcinoma, the administration of
MMI-270 was terminated because of its poor tolerance
and the side effect of joint and muscle pain.[78]
3.3. Tetracycline derivatives
Tetracycline derivatives inhibit not only MMP activity
but also MMP production. Specifically, by chelating
with zinc atoms at the MMP binding site, tetracycline
blocks the activity of mature MMPs, interferes with the
hydrolysis and activation of pro-MMP proteins, reduces
MMP expression, and protects MMPs from proteolytic
and oxidative degradation.[79,80] The family of tetracy-
cline derivatives involves classic tetracycline antibiotics,
such as doxycycline, and newer tetracycline analogs
(that have been chemically modified to eliminate their
antimicrobial activity), such as Col-3 (metastat).
3.3.1. Doxycycline
Doxycycline is a type of classic antimicrobial tetracy-
cline and has been widely studied as an anticancer
agent.[81,82] Doxycycline inhibits the secretion of
MMP-2 and MMP-9 and noncompetitively inhibits the
activity of MMP-2 and MMP-9 in breast carcinoma cells.
[83] In in vitro studies, doxycycline has inhibited the
proliferation of cancer cells and induced cell apoptosis,
reducing their ability to invade and metastasize.[81,83–
87] In an in vivo study, doxycycline combined with
batimastat enhanced the inhibition of tumor metasta-
sis.[46] However, in a phase II clinical trial on treating
renal cell carcinoma, the administration of doxycycline
and interferon-αdid not improve the clinical result.[88]
3.3.2. Metastat (CMT-3; Col-3)
Metastat is one of the chemically modified tetracyclines
which can inhibit the activity of MMP-1, MMP-2, MMP-8,
MMP-9, and MMP-13. In the metastatic prostate cancer
model, metastat inhibited cell proliferation, invasion,
tumor growth, and metastasis.[85,89] In a phase I trial,
metastat exerted an antitumor effect on the soft tissue
sarcoma.[90] Moreover, in the pharmacokinetic study of
metastat, Syed et al. found that the values for median
time at which peak plasma concentration is achieved
and ranges on both days 1 and 29 were identical.[90]
However, in the phase II trial, no objective responses
were observed in patients with advanced and/or meta-
static soft tissue sarcoma.[91]
3.4. Bisphosphonates
BPs, also known as diphosphonates, are used to prevent
bone mass loss and treat osteoporosis. After being used
for several years on human beings, BPs have been verified
as having low toxicity and high tolerance and have exhib-
ited the potential to be used in treating MMP-related
human diseases. BPs can inhibit MMP-1, MMP-2, MMP-3,
MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, and MMP-14.
Additionally, they can inhibit TIMP-2 from degrading
MMP-2 and enhance the inactivation of MMP-2.[92] The
degree of tumor cell invasion can also be reduced.[93]
Recent studies have reported that BP compounds and
zoledronic acid (zoledronate) can inhibit the growth,
migration, and invasion of breast cancer cells [94] and
improve outcomes for breast cancer patients.[95]
4. Conclusion
Although many valuable studies have explored the role
of MMPs in cancer, the regulatory role of MMPs has not
been fully clarified. Despite the incomplete data, MMPs
can be used as the auxiliary marker for diagnosing
cancer metastasis. MMPs are the new therapeutic tar-
gets of cancer; developing drugs that can inhibit the
generation and activity of MMPs can contribute to inhi-
biting cancer progression and enhancing treatment
efficacy. Numerous MMPIs have been applied to clinical
trials to verify their efficacy for cancer treatment.
However, no promising targeted drug therapies have
been used to inhibit MMPs for cancer treatment.
Further research is required to explore the potential
development of MMPIs and their effects on disease
diagnosis and treatment.
5. Expert opinion
Studies on conventional anticancer drugs have empha-
sized how cancer cells are killed by chemical com-
pounds. However, metastasis is one of the primary
factors resulting in patient death.[3] Numerous studies
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have reported that MMPs expedite cancer progression
by increasing the growth, migration, invasion, metasta-
sis, and angiogenesis of cancer cells. In normal organ-
isms, a dynamic balance between MMPs and TIMPs (i.e.
the endogenous inhibitor for MMPs) is maintained to
ensure the normal functioning of the organisms.
However, such balance may be destroyed by cancer,
resulting in the high expression of MMPs. Thus, inhibit-
ing the activity of MMPs is a reasonable method of
cancer treatment.
Most MMPIs have produced promising results in
preclinical studies; however, no significant results have
been observed in current clinical trials. This may have
occurred for several reasons. For example, MMP biology
is different between human beings and experimental
animals, inhibiting MMPs is more effective in metastasis
prevention than in reducing tumor size, drug dosage is
determined according to the severity of side effects
instead of the inhibition of tissue penetration or cataly-
tic activity, and the specific expression of MMPs in
tumors was still unclear at the trial design stage.[96]
Moreover, because the catalytic sites of most MMPs
have high homology, MMPIs lack specificity and, there-
fore, cannot be specifically applied to various types of
MMPs. The nonspecific binding effect may cause an
MMP to be bound to other MMPs necessary to the
organisms. Because a variety of MMPs are diluted, the
effective dosage for the human body may be higher
than expected. Clinically, the failed application of
MMPIs to cancer treatment may result from their lack
of selectivity for MMPs. Therefore, developing MMPIs
that have selectivity is a new direction for cancer treat-
ment. For example, the peptides or blocking antibodies
that can modulate exosite-mediated cell surface inter-
actions and functions in many potential alternative
enzyme domains may present as targets for designing
highly selective MMPIs.[7] Moreover, in contrast to all
other secreted MMPs, pro-MMP-9 and pro-MMP-2 bind
to TIMPs through their hemopexin domain.[97,98]
Those studies suggest that inhibition either substrate
binding or proenzyme activation of MMPs may all
potentially applied for MMPs targeting therapy. The
hemopexin domain of MMP-2 and MMP-9 may be a
viable target to specific abrogates their functions.
Development of the specific peptide or antibodies in
targeting the hemopexin domain of MMPs may be a
new therapeutic direction in targeting cancers.
Declaration of Interest
The author has no relevant affiliations or financial involve-
ment with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, con-
sultancies, honoraria, stock ownership or options, expert tes-
timony, grants or patents received or pending, or royalties.
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